Vasoconstrictive dihydrobenzopyran derivatives

ABSTRACT

The present invention is concerned with compounds of formula ##STR1## the pharmaceutically acceptable acid addition salts thereof, and the stereochemically isomeric forms thereof, wherein R 1  is hydrogen or C 1-6  alkyl; R 2  is hydrogen or C 1-6  alkyl; R 3  is hydrogen or C 1-6  -alkyl; R 4  is hydrogen, halo, C 1-6  alkyl, hydroxy, C 1-6  alkyloxy, aryloxy or arylmethoxy; R 5  and R 6  designate R 5a  and R 6a  wherein R 5a  and R 6a  taken together form a bivalent radical; or R 5  and R 6  can designate R 5b  and R 6b  wherein R 5b  is hydrogen and R 6b  is a heterocycle or an optionally substituted alkenyl or alkynyl group; or R 5  and R 6  designate R 5c  and R 6c , wherein R 5c  and R 6c  are hydrogen, halo, C 1-6  alkyl, C 3-6  alkenyl, C 3-6  alkynyl, hydroxy, C 1-6  alkyloxy, cyano, aminoC 1-6  alkyl, carboxyl, C 1-6  alkyloxycarbonyl, nitro, amino, aminocarbonyl, C 1-6  alkylcarbonylamino, or mono-di(C 1-6  alkyl)amino; Q is a heterocyclic ring containing at least one nitrogen atom or a radical of formula ##STR2## pharmaceutical compositions, preparations and use as a medicine are also described.

This application is a con of Ser. No. 08/586,760 filed Jan. 30, 1996,now U.S. Pat. No. 5,824,682.

The present invention relates to novel dihydrobenzopyran derivatives,processes for their preparations, pharmaceutical compositions containingthem and their use as a medicine, in particular for the preventionand/or treatment of disorders characterized by excessive vasodilatation,especially migraine.

Migraine is a non-lethal disease suffered by one in ten individuals. Themain symptom is headache; other symptoms include vomiting andphotophobia. For many years the most widely used treatment for migraineinvolved the administration of ergotalkaloids, which show howeverseveral adverse side effects. Recently a tryptamine derivative, i.e.sumatriptan, was introduced as a novel antimigraine drug. We have nowsurprisingly found that the present novel dihydrobenzopyran derivativesshow 5-HT₁ -like agonistic activity and can thus be used in thetreatment of disorders characterized by excessive vasodilatation,especially migraine.

The present invention is concerned with compounds of formula ##STR3##the pharmaceutically acceptable acid or base addition salts thereof, andthe stereochemically isomeric forms thereof, wherein

R¹, R² and R³ each independently are hydrogen or C₁₋₆ alkyl;

R⁴ is hydrogen, halo, C₁₋₆ alkyl, hydroxy, C₁₋₆ alkyloxy, aryloxy orarylmethoxy;

R⁵ and R⁶ designate R^(5a) and R^(6a),

wherein R^(5a) and R^(6a) are taken together to form a bivalent radical,which is linked to the 7 and 8 position of the dihydrobenzopyran moiety,and has the formula ##STR4## in these bivalent radicals one or twohydrogen atoms may be substituted with C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl orC₁₋₆ alkyl-S(O)--;

n is 3 or 4;

each X independently is --O--, --S--, --S(O)--, --S(O)₂ --, --C(O)--,--NR⁷ --;

each m independently is 2 or 3;

each Y independently is --O--, --S--, --S(O)--, --S(O)₂ --, --C(O)--,--NR⁷ --;

Z is --O--C(O)--, --C(O)--O--, --NH--C(O)--, --C(O)--NH--;

each t independently is 1 or 2;

R⁷ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl or C₁₋₆ alkyl-S(O)--,

each A independently is hydroxy, C₁₋₆ alkyl, C₁₋₆ alkyloxy;

or R⁵ and R⁶ designate R^(5b) and R^(6b), wherein R^(5b) is hydrogen andR^(6b) is hydroxyC₁₋₆ alkyl, carboxylC₁₋₆ alkyl, C₁₋₆alkyloxycarbonylC₁₋₆ alkyl, trihalomethyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkyloxycarbonylC₁₋₆ alkyl-S--, carboxylC₁₋₆ alkyl-S--, C₁₋₆ alkyl-S--,C₁₋₆ alkyl-S(O)--, aryl-S--, aryl-S(O)-- or R^(6b) is a radical offormula ##STR5## R⁸ and R⁹ each independently are hydrogen, carboxyl,C₁₋₆ alkyloxycarbonyl, aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl;

R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ each independently arehydrogen, halo or C₁₋₆ alkyl;

R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴ and R²⁵ each independently arehydrogen or C₁₋₆ alkyl;

or R⁵ and R⁶ designate R^(5c) and R^(6c) in which case R⁴ can only meanhydrogen;

and R^(5c) and R^(6c) each independently are hydrogen, halo, C₁₋₆ alkyl,C₃₋₆ alkenyl, C₃₋₆ alkynyl, hydroxy, C₁₋₆ alkyloxy, cyano, aminoC₁₋₆alkyl, carboxyl, C₁₋₆ alkyloxycarbonyl, nitro, amino, aminocarbonyl,C₁₋₆ alkylcarbonylamino, or mono- or di(C₁₋₆ alkyl)amino;

Alk¹ is C₁₋₅ alkanediyl;

Alk² is C₂₋₁₅ alkanediyl;

Q is a radical of formula ##STR6## wherein R²⁶ is hydrogen, cyano,aminocarbonyl or C₁₋₆ alkyl;

R²⁷ is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, C₃₋₆ cycloalkylor arylC₁₋₆ alkyl;

R²⁸ is hydrogen or C₁₋₆ alkyl; or

R²⁷ and R²⁸ taken together form a bivalent radical of formula --(CH₂)₄--, --(CH₂)₅ --, or a piperazine which is optionally substituted withC₁₋₆ alkyl;

R²⁹, R³⁰, R³¹, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶,R⁵³, R⁵⁴ and

R⁵⁵ each independently are hydrogen, hydroxy, halo, C₁₋₆ alkyl, C₁₋₆alkyloxy, aryloxy, arylC₁₋₆ alkyl, C₁₋₆ alkylthio, cyano, amino, mono-or di(C₁₋₆ alkyl)amino, mono- or di(C₃₋₆ cycloalkyl)amino,aminocarbonyl, C₁₋₆ alkyloxycarbonylamino, C₁₋₆ alkylaminocarbonylamino,piperidinyl, pyrrolidinyl;

R³², R³⁵ and R⁵² each independently are hydrogen, C₁₋₆ alkyl, C₁₋₆alkylcarbonyl, or arylC₁₋₆ alkyl;

q is 1, 2 or 3;

R³³ and R³⁴ are each hydrogen or taken together with the carbon atom towhich they are connected they can form C(O);

r is 1, 2 or 3;

R⁴⁷ and R⁴⁸ are each hydrogen or taken together with the carbon atom towhich they are connected they can form C(O);

R⁴⁹ is hydrogen, halo or C₁₋₆ alkyl;

R⁵⁰ is hydrogen and R⁵¹ is hydroxy; or R⁵⁰ and R⁵¹ taken together mayform a bivalent radical of formula (CH₂)₃ or (CH₂)₄ which is optionallysubstituted with C₁₋₆ alkyl; aryl is phenyl optionally substituted withhydroxy, halo, C₁₋₆ alkyl, C₁₋₆ alkyloxy; with the proviso that when R⁴is hydrogen and R⁵ and R⁶ designate R^(5c) and R^(6c) then Q must be aradical of formula (gg); (hh); (ii); (jj); (kk); (ll); (mm); (nn); aradical of formula (aa) wherein R²⁷ is C₃₋₆ cycloalkyl or arylC₁₋₆-alkyl; a radical of formula (aa) wherein R²⁷ and R²⁸ taken togetherwith the nitrogen atom to which they are attached form a piperazinewhich is optionally substituted with C₁₋₆ alkyl; a radical of formula(bb) wherein R²⁹ is hydroxy on a carbon atom adjacent to a nitrogenatom; a radical of formula (dd) wherein R³⁵ is hydrogen and R³³ and R³⁴taken together with the carbon atom to which they are attached formC(O); a radical of formula (ee) wherein R⁵⁵ is arylC₁₋₆ alkyl.

Some of the compounds of formula (I) may also exist in their tautomericforms. Such forms although not explicitly indicated in the above formulaare intended to be included within the scope of the present invention.

As used in the foregoing definitions and hereinafter halo definesfluoro, chloro, bromo and iodo; C₁₋₆ alkyl defines straight and branchchained saturated hydrocarbon radicals having from 1 to 6 carbon atomssuch as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl andthe like; C₃₋₆ alkenyl defines straight and branch chained hydrocarbonradicals containing one double bond and having from 3 to 6 carbon atoms,such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl,3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom of saidC₃₋₆ alkenyl being connected to a nitrogen atom preferably is saturated,C₃₋₆ alkynyl defines straight and branch chained hydrocarbon radicalscontaining one triple bond and having from 3 to 6 carbon atoms, such as,for example, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl,3-hexynyl, and the like; and the carbon atom of said C₃₋₆ alkynylradicalbeing connected to a nitrogen atom preferably is saturated; C₃₋₆cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl; C₁₋₅ alkanediyl defines bivalent straight and branch chainedsaturated hydrocarbon radicals having form 1 to 5 carbon atoms, such as,for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediylor 1,5-pentanediyl and the branched isomers thereof; C₂₋₁₅ alkanediyldefines bivalent straight and branch chained saturated hydrocarbonradicals having from 2 to 15 carbon atoms such as, for example,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl,1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl,1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl,1,13-tridecanediyl, 1,14-tetradecanediyl, 1,15-pentadecanediyl, and thebranched isomers thereof. The terms C₁₋₄ alkanediyl, C₂₋₆ alkanediyl andC₂₋₄ alkanediyl are defined in an analogous manner. The term "C(O)"refers to a carbonyl group.

The pharmaceutically acceptable acid addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The latter can conveniently be obtained by treating the base formwith such appropriate acids as inorganic acids, for example, hydrohalicacids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid;nitric acid, phosphoric acid and the like; or organic acids, forexample, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic,2-oxopropanoic, ethanedioic, propanedioic, butanedioic,(Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, ethanesulfonic, benzenesulfonic,4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic,4-amino-2-hydroxybenzoic and the like acids. Conversely the salt formcan be converted by treatment with alkali into the free base form.

The compounds of formula (I) containing acidic protons may also beconverted into their therapeutically active non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salt forms comprise, for example, the ammoniumsalts, the alkali and earth alkaline metal salts, e.g. the lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabaminesalts, and salts with amino acids such as, for example, arginine, lysineand the like. Conversely the salt form can be converted by treatmentwith acid into the free acid form.

The term addition salt also comprises the hydrates and solvent additionforms which the compounds of formula (I) are able to form. Examples ofsuch forms are e.g. hydrates, alcoholates and the like.

The term "stereochemically isomeric forms" as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure. More inparticular, stereogenic centers may have the R- or S-configuration;substituents on bivalent cyclic saturated hydrocarbon radicals may haveeither the cis- or trans-configuration and C₃₋₆ alkenyl radicals mayhave the E- or Z-configuration. Stereochemically isomeric forms of thecompounds of formula (I) are obviously intended to be embraced withinthe scope of this invention.

R¹ is suitably methyl or hydrogen, preferably R¹ is hydrogen;

R² is suitably methyl or hydrogen, preferably R² is hydrogen;

R³ is suitably methyl or hydrogen, preferably R³ is hydrogen;

R⁴ is suitably hydrogen, C₁₋₆ alkyl or C₁₋₆ alkyloxy, preferably R⁴ ishydrogen;

when R⁵ and R⁶ designate R^(5a) and R^(6a),

then R^(5a) and R^(6a) suitably form a bivalent radical of formula (a1),(a2), (a3), (a4), (a7), (a8), (a11) or (a12);

X is suitably O, S or S(O)₂, preferably X is O or S(O)₂ ;

Y is suitably O or S, preferably Y is O;

Z is suitably --O--C(O)-- or --C(O)--O--;

when R⁵ and R⁶ designate R^(5b) and R^(6b),

then R^(6b) suitably is hydroxyC₁₋₆ alkyl, trihalomethyl, or a radicalof formula (b1), (b2), (b3), (b4), (b5), (b6) or (b13);

R^(6b) preferably is in the 8-position of the dihydrobenzopyran moiety;

R⁸ is suitably hydrogen or C₁₋₆ alkyloxycarbonyl, preferably R⁶ ishydrogen;

R⁹ is suitably hydrogen or C₁₋₆ alkyloxycarbonyl, preferably R⁷ ishydrogen or methyloxycarbonyl;

R¹⁰ and R¹¹ each independently are suitably hydrogen or C₁₋₆ alkyl,preferably R¹⁰ and R¹¹ are hydrogen or methyl;

R¹² and R¹³ each independently are suitably hydrogen or hydroxy;

R¹⁴ and R¹⁵ each independently are suitably hydrogen or C₁₋₆ alkyl,preferably R¹⁴ and R¹⁵ are hydrogen;

R¹⁶ and R¹⁷ each independently are hydrogen or C₁₋₆ alkyl, preferablyR¹⁶ and R¹⁷ are both hydrogen;

R¹⁸, R¹⁹, R²⁰, R²¹, R²², R²³, R²⁴ and R²⁵ are preferably hydrogen;

when R⁵ and R⁶ designate R^(5c) and R^(6c) ;

then R^(5c) and R^(6c) suitably are hydrogen, halo, or C₁₋₆ alkyl,preferably R^(5c) and R^(6c) are hydrogen, chloro, fluoro, methyl orethyl;

Alk¹ is suitably C₁₋₃ alkanediyl, preferably Alk¹ is methylene;

Alk² is suitably C₂₋₆ alkanediyl, preferably Alk² is 1,3-propanediyl;

when Q is a radical of formula (aa),

R²⁶ is suitably hydrogen, cyano, aminocarbonyl or methyl, preferably R²⁶is hydrogen or cyano;

R²⁷ is suitably hydrogen or C₁₋₆ alkyl, preferably R²⁷ is hydrogen,methyl or ethyl;

R²⁸ is suitably hydrogen or C₁₋₆ alkyl, preferably R²⁸ is hydrogen ormethyl;

a radical of formula (bb),

R²⁹ and R³⁰ each independently are suitably hydrogen, hydroxy, halo,methyl, preferably both R²⁹ and R³⁰ are hydrogen or R²⁹ is hydrogen andR³⁰ is hydroxy;

a radical of formula (cc),

R³¹ is suitably hydrogen, hydroxy, preferably R³¹ is hydrogen;

R³² is suitably hydrogen, or phenylmethyl, preferably R³² is hydrogen;

a radical of formula (dd),

q is preferably 2;

R³³ and R³⁴ are both preferably hydrogen;

R³⁵ is suitably hydrogen or phenylmethyl, preferably R³⁵ is hydrogen;

a radical of formula (ee),

R³⁶ is suitably hydrogen, halo or methyl, preferably R³⁶ is hydrogen orchloro;

R⁵⁵ is suitably hydrogen or phenylmethyl;

a radical of formula (ff),

R³⁷ and R³⁸ each independently suitably are hydrogen, halo or methyl,preferably R³⁷ and R³⁸ are hydrogen or chloro;

a radical of formula (gg),

R³⁹ and R⁴⁰ each independently suitably are hydrogen, hydroxy, chloro ormethyl, preferably R³⁹ and R⁴⁰ are both hydrogen or R³⁹ is hydrogen andR⁴⁰ is hydroxy;

a radical of formula (hh),

R⁴¹ and R⁴² each independently suitably are hydrogen, hydroxy, halo ormethyl, preferably R⁴¹ and R⁴² are both hydrogen or R⁴¹ is hydrogen andR⁴² is chloro;

a radical of formula (ii),

R⁴³ and R⁴⁴ each independently suitably are hydrogen, halo, C₁₋₆alkyloxy, C₁₋₆ alkylthio, amino, mono- or di(C₁₋₆ alkyl)amino,preferably R⁴³ is hydrogen, chloro, methylthio or amino and R⁴⁴ ishydrogen;

a radical of formula (jj),

R⁴⁵ and R⁴⁶ each independently suitably are hydrogen, halo, C₁₋₆ alkyl,preferably

R⁴⁵ and R⁴⁶ are hydrogen or chloro;

a radical of formula (kk),

r preferably is 2;

R⁴⁷ and R⁴⁸ both preferably are hydrogen;

a radical of formula (ll),

R⁴⁹ is suitably hydrogen or methyl, preferably hydrogen;

a radical of formula (mm),

R⁵⁰ and R⁵¹ taken together suitably form a bivalent radical of formula(CH₂)₄ ;

R⁵² suitably is hydrogen;

a radical of formula (nn),

R⁵³ is suitably hydrogen and R⁵⁴ suitably is hydroxy; and

aryl is preferably phenyl.

A group of special compounds are those compounds of formula (I) whereinR¹, R², R³ and R⁴ are as defined under formula (I) and wherein R⁵ and R⁶designate R^(5a) and R^(6a), wherein in formulas (a7) and (a8) t is 2; Qis a radical of formula (aa), (bb), (cc), (dd) wherein q is 1 or 2, (ee)wherein R⁵⁵ is hydrogen, (ff), (gg), (hh), (ii), (jj), (kk) wherein q is1 or 2, (ll).

Another group of special compounds are those compounds of formula (I)wherein R¹, R², R³ are as defined under formula (I), R⁴ is hydrogen,halo, C₁₋₆ alkyl; R⁵ and R⁶ designate R^(5b) and R^(6b), R^(5b) beinghydrogen and R^(6b) is hydroxyC₁₋₆ alkyl, carboxylC₁₋₆ alkyl, C₁₋₆alkyloxycarbonylC₁₋₆ alkyl, trihalomethyl, a radical of formula (b1),(b2), (b3), (b4), (b5), (b6), (b7), (b8), (b9), (b10), (b11), (b12); Qis a radical of formula (aa), (bb), (cc), (dd) wherein q is 1 or 2, (ee)wherein R⁵⁵ is hydrogen, (ff), (gg), (hh), (ii), (jj), (kk) wherein q is1 or 2, or (ll).

Still another group of special compounds are those compounds of formula(I) wherein R¹, R², R³ are as defined under formula (I), R⁴ is hydrogenand R⁵ and R⁶ designate R^(5c) and R^(6c), and Q is a radical of formula(gg); (hh); (ii); (jj); (kk) wherein q is 1 or 2; (ll); a radical offormula (bb) wherein R²⁹ is hydroxy on a carbon atom adjacent to anitrogen atom; or a radical of formula (dd) wherein R³⁵ is hydrogen andR³³ and R³⁴ taken together with the carbon atom to which they areattached form C(O) and q is 1 or 2.

Interesting compounds are those compounds of formula (I), wherein R² ishydrogen.

Also interesting compounds are those compounds of formula (I) wherein R³is hydrogen.

Particular compounds are those compounds of formula (I) wherein R⁵ andR⁶ designate R^(5a) and R^(6a) and Q is a radical of formula (bb)wherein R²⁹ and R³⁰ are hydrogen; or Q is a radical of formula (dd)wherein q is 1 or 2 and R³¹ and R³² are both hydrogen.

Also particular compounds are those compounds of formula (I) wherein R⁵and R⁶ designate R^(5b) and R^(6b), R^(5b) being hydrogen and R^(6b) isC₁₋₆ alkyloxycarbonyl-C₁₋₆ akyl, trihalomethyl, C₁₋₆alkyloxycarbonyl-C₁₋₆ alkyl-S--, C₁₋₆ alkyl-S--, aryl-S--, aryl-S(O)--,or R^(6b) is a radical of formula (b1), wherein R⁸ is hydrogen; (b2)wherein R⁹ is C₁₋₆ alkyloxycarbonyl; (b3) wherein R¹⁰ and R¹¹ both beinghydrogen; (b4) wherein R¹² and R¹³ are both hydrogen; (b5) wherein R¹⁴and R¹⁵ are both hydrogen; (b6) R¹⁶ is hydrogen or halo and R¹⁷ ishydrogen; or (b13) wherein R²⁵ is hydrogen; Q is a radical of formula(bb) wherein R²⁹ and R³⁰ are hydrogen; or Q is a radical of formula (dd)wherein q is 1 or 2 and R³¹ and R³² are both hydrogen.

Still other particular compounds are those compounds of formula (I)wherein R⁴ is hydrogen; R⁵ and R⁶ designate R^(5c) and R^(6c), R^(5c)being hydrogen and R^(6c) is hydrogen, halo, C₁₋₆ alkyl or C₁₋₆alkyloxy; Q is a radical of formula (aa) wherein R²⁶ is hydrogen, cyanoor aminocarbonyl, R²⁷ is arylC₁₋₆ alkyl and R²⁸ is hydrogen or C₁₋₆alkyl, or R²⁷ and R²⁸ taken together with the nitrogen atom to whichthey are attached form are piperazine ring which is N-substituted withC₁₋₆ alkyl; a radical of formula (bb) wherein R²⁹ is hydroxy on a carbonatom adjacent to a nitrogen atom; a radical of formula (dd) wherein R³⁵is hydrogen and R³³ and R³⁴ taken together with the carbon atom to whichthey are attached form C(O); a radical of formula (ee) wherein R³⁶ ishydroxy and R⁵⁵ is arylC₁₋₆ alkyl; a radical of formula (gg) wherein R³⁹and R⁴⁰ each independently are hydrogen, C₁₋₆ alkyl or aminocarbonyl; aradical of formula (hh) wherein R⁴¹ and R⁴² each independently arehydrogen, halo, hydroxy, C₁₋₆ alkyl or aminocarbonyl; a radical offormula (ii) wherein R⁴⁴ is hydrogen and R⁴³ is hydrogen, C₁₋₆ alkyloxy,C₁₋₆ alkylthio, amino, mono- or di(C₁₋₆ alkyl)amino, piperidinyl; aradical of formula (jj) wherein R⁴⁵ and R⁴⁶ are both hydrogen; a radicalof formula (kk) wherein R⁴⁷ and R⁴⁸ are both hydrogen; radical offormula (ll) wherein R⁴⁹ is hydrogen; a radical of formula (mm) whereinR⁵⁰ is hydrogen, R⁵¹ is hydroxy or R⁵⁰ and R⁵¹ taken together form abivalent radical of formula CH₂)₄ and R⁵² is hydogen; or a radical offormula (nn) wherein R⁵³ is hydrogen and R⁵⁴ is hydroxy.

Preferred compounds are:

N-[(2,3,4,7,8,9-hexahydrobenzo[2,1-b:3,4-b']dipyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine;N-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine;(±)-N-[(2,3,4,8,9,10-hexahydrobenzo[2,1-b:3,4-b']dipyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine;N-[(3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine;N-(4,5-dihydro-1H-imidazol-2-yl)-N'-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-1,3-propanediamine;N-[(2,3,4,7,8,9-hexahydrobenzo[2,1-b:3,4-b']dipyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-[(2,3,7,8-tetrahydro-9H-pyrano[2,3-f]-1,4-benzodioxin-9-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-[(3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;methyl3-[6-fluoro-3,4-dihydro-2-[[[3-(2-pyrimidinylamino)propyl]amino]methyl]-2H-1-benzopyran-8-yl]-2-propenoate;N-[[6-fluoro-8-(2-furanyl)-3,4-dihydro-2H-1-benzopyran-2-yl]methyl]-N'-2-pyrimidinyl-1,3-propanediamine;N-[[6-fluoro-3,4-dihydro-8-(2-thienyl)-2H-1-benzopyran-2-yl]methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(3,4,5,6-tetrahydro-2-pyridinyl)-1,3-propanediamine;N⁴-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]-N2-methyl-2,4-pyrimidinediamine,the pharmaceutically acceptable acid addition salts thereof and thestereochemically isomeric forms thereof.

The compounds of formula (1) can generally be prepared by reacting adiamine of formula (II) with a reagent of formula (III) wherein W¹ is areactive leaving group such 30 as, for example, halo, e.g. chloro,bromo; alkyloxy, e.g. methoxy, ethoxy and the like; aryloxy, e.g.phenoxy and the like; alkylthio, e.g. methylthio, ethylthio and thelike; arylthio, e.g. benzenethio and the like.

In the formulas (II), (III) and all the following formulas the variabelsR¹, R², R³, R⁴, R⁵, R⁶, Alk¹, Alk², and Q are as defined under formula(I) unless specifically described otherwise. ##STR7##

Said reaction can be performed by stirring the diamine of formula (II)with the reagent of formula (III) in an appropriate solvent such as, forexample, an alcohol, e.g. ethanol and the like; a halogenatedhydrocarbon, e.g. trichloromethane and the like or an ether, e.g.tetrahydrofuran, 1,4-dioxane and the like; an aromatic hydrocarbon, e.g.methylbenzene and the like or mixtures thereof. Optionally a base, suchas, for example, an alkalimetal carbonate, e.g. sodium or potassiumcarbonate; an alkalimetal hydrogen carbonate, e.g. sodium or potassiumhydrogen carbonate; an appropriate organic base, e.g.N,N-diethylethanamine, pyridine and the like bases, can be added to pickup the acid that may be formed during the course of the reaction.Elevated temperatures may enhance the rate of the reaction. Preferablythe reaction is performed at the reflux temperature of the reactionmixture.

The compounds of formula (I) can also generally be prepared by reductiveN-alkylation of an aminoderivative of formula (VI) with an appropriatealdehyde of formula (V), wherein Alk³ is a direct bond or C₁₋₄alkanediyl. ##STR8## Said reaction is performed by stirring thereactants in an appropriate solvent such as, for example, an alcohol,e.g. ethanol and the like; an ether, e.g. tetrahydrofuran and the like;an aromatic solvent, e.g. methylbenzene and the like, or mixturesthereof. Optionally a water separator can be used to remove the waterthat is formed during the course of the reaction. The resulting iminecan then be reduced by reactive hydride reagents such as, for example,sodium borohydride, or by catalytic hydrogenation on an appropriatecatalyst, such as, for example palladium on charcoal, platinum oncharcoal, Raney nickel and the like in a suitable solvent, such as, forexample an alcohol, e.g. methanol, ethanol and the like; an ether, e.g.tetrahydrofuran, and the like; a carboxylic ester, e.g. ethyl acetate,butyl acetate and the like; or a carboxylic acid, e.g. acetic acid,propanoic acid and the like. Optionally the reaction may be performed atelevated temperatures and/or pressures.

The intermediate aldehyde of formula (V) can be prepared by reducing anacyl derivative of formula (IV) wherein Alk³ is defined as above. Theacyl halide can be prepared by reacting the corresponding acid, with ahalogenating reagent such as thionylchloride, phosphorus trichloride,phosphorus tribromide, oxalylchloride and the like. The latter reactionmay be performed in an excess of the halogenating reagent or inappropriate solvents such as for example halogenated hydrocarbons, e.g.dichloromethane, trichloromethane and the like; aromatic hydrocarbons,e.g. methylbenzene and the like; ethers, e.g. tetrahydrofuran,1,4-dioxane and the like, or dipolar aprotic solvents, e.g.N,N-dimethylformamide, N,N-dimethylacetamide and the like. Stirring andelevated temperatures may be appropriate to enhance the rate of thereaction.

Said reduction of the acylhalide of formula (IV) can for instance beperformed by catalytic hydrogenation with a catalyst such as palladiumon charcoal, palladium on bariumsulfate, platinum on charcoal and thelike in appropriate solvents such as, for example ethers, e.g.tetrahydrofuran and the like; preferably in admixture with a dipolaraprotic solvent, such as, for example N,N-dimethylformamide,N,N-dimethylacetamide and the like. Optionally a catalyst poison can beadded, such as thiophene, quinoline-sulfur and the like.

The reaction sequence starting from the intermediate of formula (IV) andyielding compounds of formula (I) may be performed as a one-potprocedure. The intermediates of formula (V) wherein R⁵ and R⁶ designateR^(5a) and R^(6a) are defined as intermediates of formula (V-a);intermediates of formula (V) wherein R⁵ and R⁶ designate R^(5b) andR^(6b) are defined as intermediates of formula (V-b). The intermediatesof formula (V-a) and (V-b) are deemed novel.

The compounds of formula (I) can also be prepared by reductiveN-alkylation of an amine of formula (IX) with an aldehyde of formula(X), wherein Alk⁴ is C₂₋₁₄ alkanediyl. The reaction conditions aresimilar to those described for the reaction of intermediates of formula(V) with those of formula (VI). ##STR9##

The intermediates of formula (IX) wherein R⁵ and R⁶ designate R^(5a) andR^(6a) are indicated hereinunder as intermediates of formula (IX-a);intermediates of formula (IX) wherein R⁵ and R⁶ designate R^(5b) andR^(6b) are indicated hereinunder as intermediates of formual (IX-b). Theintermediates of formula (IX-a) and (IX-b) are deemed novel.

The compounds of formula (I) can also be prepared by N-alkylating anamine of formula (VI) with an intermediate of formula (VII), wherein W²is a reactive leaving group such as, for example, halo, e.g. chloro,bromo or iodo; sulfonyloxy, e.g. methanesulfonyloxy,methylbenzenesulfonyloxy and the like, in appropriate solvents such asketones, e.g. 2-butanone and the like; ethers, e.g. tetrahydrofuran andthe like; aromatic hydrocarbons, e.g. methylbenzene and the like;dipolar aprotic solvents, e.g. N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide and the like. ##STR10##

Stirring and heating may enhance the reaction rate. Optionally asuitable base may be added to pick up the acid that is formed during thecourse of the reaction, such as, for example an alkali metal carbonate,e.g. sodium or potassium carbonate; an alkali metal hydrogen carbonate,e.g. sodium or potassium hydrogen carbonate and the like; an appropriateorganic base, e.g. N,N-diethylethanamine, pyridine and the like.

The intermediates of formula (VII) wherein R⁵ and R⁶ designate R^(5a)and R^(6a) are indicated hereinunder as intermediates of formula(VII-a); intermediates of formula (VII) wherein R⁵ and R⁶ designateR^(5b) and R^(6b) are indicated hereinunder as intermediates of formual(VII-b). The intermediates of formula (VII-a) and (VII-b) are deemednovel.

The compounds of formula (I), wherein R² is hydrogen, said compoundsbeing represented by formula (I'), may be prepared by debenzylation ofan intermediate of formula (VIII). ##STR11##

Said debenzylation can be performed following art-known procedures suchas catalytic hydrogenation using appropriate catalysts, e.g. platinum oncharcoal, palladium on charcoal, in appropriate solvents such asalcohols, e.g. methanol, ethanol, 2-propanol and the like; ethers e.g.1,1'-oxybisethane, tetrahydrofuran, 2,2'-oxybispropane and the like.Optionally elevated temperatures and pressures may be applied.

Compounds of formula (I) wherein R⁵ and R⁶ designate R^(5b) and R^(6b)are indicated as compounds of formula (I-b). Compounds of formula (I-b)may be prepared by aromatic substitution of a halosubstited, preferablyiodosubstituted, dihydrobenzopyran derivative of formula (XI). Saidaromatic substitution may, for instance, be carried out with a reagentof formula (XII) in suitable solvent and in the presence of anappropriate catalyst, such as, for example,tetrakis(triphenylphosphine)palladium. ##STR12##

The compounds of formula (I), can also be converted into each other byfunctional group transformations. For instance the compounds of formula(I), wherein Q represents a pyrimidinyl or a pyridinyl moiety can beconverted into the tetrahydroanalogs following art-known catalytichydrogenation procedures. Furthermore, compounds of formula (I) bearinga C₃₋₆ alkynylgroup or C₃₋₆ alkenylgroup can be converted into thecorresponding compounds bearing C₁₋₆ alkylgroup following art-knownhydrogenation techniques. Compounds of formula (I) bearing a cyanogroupcan be converted into the corresponding compounds bearing an aminomethylsubstituent following art-known hydrogenation techniques. Compoundsbearing an alkyloxy substituent can be converted into compounds bearinga hydroxy group by treating the alkyloxy compound with an appropriateacidic reagent such as for example, hydrohalic acid, e.g. hydrobromicacid or borontribromide and the like. Compounds bearing an aminosubstituent can be N-acylated or N-alkylated following art-knownN-acylation or N-alklation procedures.

The intermediates mentioned hereinabove are novel and may be preparedfollowing art-known procedures which are for instance illustrated in theexperimental part.

Pure stereochemically isomeric forms of the compounds of this inventionmay be obtained by the application of art-known procedures.Diastereoisomers may be separated by physical separation methods such asselective crystallization and chromatographic techniques, e.g. liquidchromatography. Enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids. Said pure stereochemically isomeric forms may also bederived from the corresponding pure stereochemically isomeric forms ofthe appropriate starting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The compounds of formula (I), the pharmaceutically acceptableacid-addition salts and stereochemically isomeric forms thereof haveinteresting pharmacological properties: they show 5HT_(1-like) agonisticactivity. The compounds of the present invention have remarkablevasoconstrictor activity. They are useful to prevent or treat conditionswhich are related to vasodilatation. For instance, they are useful inthe treatment of conditions characterized by or associated with cephalicpain, e.g. cluster headache and headache associated with vasculardisorders, especially migraine. These compounds are also useful in thetreatment of venous insufficiency and in the treatment of conditionsassociated with hypotension.

The vasoconstrictor activity of the compounds of formula (I) can bedetermined using an in vitro-test as is described in "Instantaneouschanges of alpha-adrenoreceptor affinity caused by moderate cooling incanine cutaneous veins" in the American Journal of Physiology 234(4),H330-H337, 1978; or in the test described in the pharmacologicalexample, wherein the serotonin-like response of the compounds of thepresent invention was tested on the basilar arteries of pigs.

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes. To prepare the pharmaceutical compositions ofthis invention, an effective amount of a particular compound, in base oracid addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions: or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, to aid solubility for example, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. In the compositions suitable for percutaneous administration,the carrier optionally comprises a penetration enhancing agent and/or asuitable wetting agent, optionally combined with suitable additives ofany nature in minor proportions, which additives do not cause asignificant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. It is especially advantageous to formulate theaforementioned pharmaceutical compositions in dosage unit form for easeof administration and uniformity of dosage. Dosage unit form as used inthe specification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The compounds of the present invention therefore may be used asmedicines in conditions related to vasodilatation, more in particularhypotension, venous insufficiency and especially cephalic pain amongwhich migraine. The compounds of the present invention also provide amethod of treating warm-blooded animals suffering from conditionsrelated to vasodilatation, such as, hypotension, venous insufficiencyand especially cephalic pain among which migraine by administering aneffective amount of a compound of formula (I), a pharmaceuticallyacceptable acid addition salt or a stereoisomeric form thereof. Thoseskilled in the art could easily determine the effective amount from thetest results presented hereinafter. In general it is contemplated thatan effective amount would be from 1 μg/kg to 1 mg/kg body weight, and inparticular from 2 μg/kg to 200 μg/kg body weight. It may be appropriateto administer the required dose as two, three, four or more sub-doses atappropriate intervals throughout the day. Said sub-doses may beformulated as unit dosage forms, for example, containing 0.005 to 20 mg,and in particular 0.1 mg to 10 mg of active ingredient per unit dosageform.

The following examples are intended to illustrate and not to limit thescope of the present invention in all its aspects.

EXPERIMENTAL PART

A. Preparation of Compounds of Formula (I) Wherein R⁵ and R⁶ DesignateR^(5a) and R^(6a), and the Intermediates Thereof

EXAMPLE 1-a

a) A mixture of 2,3-dihydro-1H-inden-4-ol (0.37 mol) and aceticanhydride (0.37 mol) in sulfuric acid (300 mol) was stirred for 1 hourat room temperature. The reaction mixture was poured out into a mixtureof water and 1,1'-oxybisethane. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated, yielding 75 g (>100%crude residue) of 2,3-dihydro-1H-inden-4-ol acetate (ester) (interm.1-a).

b) Intermediate (1-a) (0.37 mol) was heated to 100° C. Aluminum chloride(200 g) was added and the reaction mixture was stirred for 1 hour at120° C. The reaction mixture was cooled and ice was added, followed by amixture of water and concentrated hydrochloric acid. This mixture wasextracted with 1,1'-oxybisethane. The organic layer was separated,treated with activated charcoal, dried (MgSO₄), filtered and thefiltrate was evaporated. The residue was purified by distillation (oilpump; 110° C.), yielding 29 g of1-(2,3-dihydro-4-hydroxy-1H-inden-5-yl)ethanone (interm. 2-a).

c) Sodium methylate (24 g) was stirred in methylbenzene (300 ml). Amixture of diethyl oxalate (0.16 mol) and intermediate (2-a) (0.16 mol)in methylbenzene (10 ml) was added dropwise. This mixture was stirredand refluxed for 2 hours. The resulting precipitate was filtered off anddried. The solid was stirred in a mixture of hydrochloric acid (10 ml)and acetic acid (500 ml). The reaction mixture was stirred and refluxedfor 1 hour. The mixture was poured out into water. The resultingprecipitate was filtered off and dried (vacuum), yielding 21 g of4,7,8,9-tetrahydro-4-oxocyclopenta[h]-benzopyran-2-carboxylic acid(interm. 3-a).

d) A mixture of intermediate (3-a) (0.09 mol) in acetic acid (200 ml)was hydrogenated with palladium on activated carbon (1 g) as a catalyst.After uptake of hydrogen (3 eq.), the catalyst was filtered off. Thesolvent was evaporated. The residue was vacuum dried, yielding 21 g of(±)-2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-carboxylic acid(interm. 4-a).

e) A mixture of intermediate (4-a) (0.11 mol) in tetrahydrofuran (250ml) was stirred under nitrogen flow. 1,1'-Carbonylbis-1H-imidazole (0.11mol) was added and the reaction mixture was stirred for 2 hours at roomtemperature. Then, it was cooled to -80° C. A solution ofdiisobutylaluminum hydride in methylbenzene (20%) (0.33 mol) was addeddropwise and the reaction mixture was stirred for 2 hours at -80° C. Themixture was decomposed with methanol, then poured out into water. Themixture was acidified, then extracted with 1,1'-oxybisethane. Theseparated organic layer was dried (MgSO₄), filtered and the solvent wasevaporated, yielding 12 g of(±)-2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-carboxaldehyde(interm. 5-a).

In a similar manner were also prepared:

(±)-2,3,7,8-tetrahydro-9H-pyrano[2,3-f]-1,4-benzodioxin-9-carboxaldehyde(interm. 6-a);

(±)-2,3,4,8,9,10-hexahydrobenzo[1,2-b:3,4-b']dipyran-2-carboxaldehyde(interm. 7-a);

(±)-2,3,4,7,8,9-hexahydrobenzo[2,1-b:3,4-b']dipyran-2-carboxaldehyde(interm. 8-a).

EXAMPLE 2-a

a) A mixture of 4-oxo-4H-naphto[1,2-b]pyran-2-carboxylic acid (12 g) and2-methoxyethanol (100 ml) was hydrogenated at normal pressure and atroom temperature in the presence of palladium on activated carbon 10% (2g) as a catalyst. After the calculated amount of hydrogen was taken up,the catalyst was filtered off and the filtrate was evaporated, yielding7g (61.4%) of 3,4-dihydro-2H-naphto[1,2-b]pyran-2-carboxylic acid(interm. 9-a).

b) A mixture of intermediate (9-a) (7 g), ethanol (160 ml) and sulfuricacid was stirred and refluxed for 1 hour. The reaction mixture wasevaporated and the oily residue was taken up in water. After treatingwith sodium hydroxide, the product was extracted with dichloromethane.The extract was dried, filtered and evaporated, yielding 5 g (63.5%) ofethyl 3,4dihydro-2H-naphto[1,2-b]pyran-2-carboxylate (interm. 10-a).

c) A mixture of intermediate (10-a) (0.03 mol) in methanol saturatedwith ammonia (200 ml) was stirred at room temperature overnight. Theprecipitate was filtered off and washed with methanol. The product wasused without further purification, yielding 6.6 g (97%) of(±)-3,4-dihydro-2H-naphtho[1,2-b]pyran-2-carboxamide (interm. 11-a).

d) A mixture of intermediate (11-a) (0.0291 mol) and sodium borohydride(0.1455 mol) in 1,4-dioxane (50 ml) was cooled till 0° C. undernitrogen. Acetic acid (0.1455 mol) in 1,4-dioxane (20 ml) was addeddropwise and the mixture was stirred and refluxed for 2 hours 30 min.The mixture was evaporated till dryness. Water was added to the residue.

The mixture was acidified with concentrated HCl and stirred for 30 min.The mixture was basified with a 50% NaOH solution and extracted withdichloromethane. The organic layer was dried, filtered off andevaporated till dryness. The residue was converted into the hydrochloricacid salt and then liberated. The residue (2.9 g) was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 9.75/0.25). Thepure fractions were collected and evaporated, yielding 2.4 g (39%)(±)-3,4-dihydro-2H-naphtho[1,2-b]pyran-2-methanamine (interm. 12-a).

In a similar manner was also prepared:

(±)-3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-methanamine (interm.13-a).

EXAMPLE 3-a

A mixture of intermediate (5-a) (0.03 mol) and benzenemethanamine (0.073mol) in 2,2'-oxybispropane (250 ml) and N,N-dimethylacetamide (10 ml)was hydrogenated with palladium on activated carbon (10%) (1 g) as acatalyst. After uptake of hydrogen (1 eq.), the catalyst was filteredoff. The filtrate was evaporated. The residue was stirred in a mixtureof water and 1,1'-oxybisethane. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated, yielding 6.5 g of(±)-2,3,4,7,8,9-hexahydro-N-(phenylmethyl)cyclopenta[h]-1-benzopyran-2-methanamine(interm. 14-a).

EXAMPLE 4-a

A mixture of intermediate (14-a) (0.02 mol) and 2-propenenitrile (0.2mol) in ethanol (100 ml) was stirred and refluxed overnight. The solventwas evaporated. The residue was dissolved in methanol. Palladium onactivated carbon (10%) (2 g) was added and the mixture was hydrogenated.After uptake of hydrogen (3 eq.), the catalyst was filtered off and thefiltrate was evaporated, yielding 5.2 g of(±)-N-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-1,3-propanediamine(interm. 15-a).

EXAMPLE 5-a

A solution of ethyl6-oxo-2,3-dimethyl-6H-furo[3,2-h][1]benzopyran-8-carboxylate (0.1 mol)in methanol (250 ml) was hydrogenated for 10 hours at 170° C.(pressurized) with palladium on activated carbon, palladium content 5%(2 g) as a catalyst in the presence of a 4% thiophene solution (10 ml).After uptake of hydrogen (3 equiv), the catalyst was filtered off andthe filtrate was evaporated. The residue was purified by flash columnchromatography over silica gel (eluent: CH₂ Cl₂). The desired fractionswere collected and the solvent was evaporated, yielding 20 g (72.9%) of(±)-ethyl7,8-dihydro-2,3-dimethyl-6H-furo[3,2-h][1]benzopyran-8-carboxylate(interm. 16-a).

EXAMPLE 6-a

A mixture of intermediate (8-a) (6.9 g impure solid) andN-2-pyrimidinyl-1,2-propanediamine (0.02 mol) in methanol (200 ml) washydrogenated with palladium on activated carbon (10%) (2 g) as acatalyst in the presence of a solution of thiophene (4%) (1 ml). Afteruptake of hydrogen (1 eq.), the catalyst was filtered off. The filtratewas evaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 95/5). The pure fractions werecollected and the solvent was evaporated. The residue was dissolved in2-propanone and converted into the ethanedioic acid salt (1:2). The saltwas filtered off and dried (vacuum; 60° C.), yielding 7.8 g (73.0%) of(±)-N-[(2,3,4,7,8,9-hexahydrobenzo[2,1-b:3,4-b']dipyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamineethanedioate (1:2); mp. 190.4° C. (comp. 1-a).

EXAMPLE 7-a

A mixture of intermediate (13-a) (0.0088 mol) and3-(2-pyrimidinylamino)propanal (0.0112 mol) in methanol (100 ml) washydrogenated with palladium on activated carbon (10%) (1 g) as acatalyst at room temperature and 3 atm. in a Parr apparatus. Afteruptake of hydrogen (1 eq.), the catalyst was filtered off and thefiltrate was evaporated till dryness. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 97/3). Thealmost pure fractions were collected and evaporated The residue waspurified again by HPLC over silica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃)95/5). The pure fractions were collected and evaporated, yielding 0.85 g(27%) of(±)-N-[(3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine;mp. 57.6° C. (comp. 5-a).

EXAMPLE 8-a

Intermediate 16a (0.072 mol) was dissolved in methylbenzene (250 ml)/H(100 ml). The solution was cooled to -70° C. Diisobutylaluminiumhydride, 1.5M solution in hexane (0.1 mol) was added dropwise and themixture was stirred for 1 hour at -70° C. Methanol (15 ml) was addeddropwise and the reaction mixture was allowed to warm to roomtemperature. The mixture was poured out into water, acidified withhydrochloric acid and extracted with diethyl ether. The separatedorganic layer was dried, filtered and the solvent evaporated. Theresidue was dissolved in methanol 1150 ml).N-2-pyrimidinyl-1,3-propanediamine (0.06 mol) was added and the mixturewas hydrogenated with palladium-on-charcoal (small amount) as a catalystin the presence of thiophene, 4% solution (10 ml). After uptake of H₂ (1equiv), the catalyst was filtered off and the filtrate was evaporated.The residue was purified by column chromatography over silica gel(eluent: CH₂ Cl₂ /CH₃ OH 90/10). Three fraction groups were collectedand the solvent was evaporated, yielding residues (1), (2) and (3) (12g). A sample of residue (3) (3.6 g) was dissolved in 2-propanone andconverted into the ethanedioic acid salt (1:2) with a solution ofethanedioic acid.H₂ O (0.020 mol) in 2-propanone. The precipitate wasfiltered off and dried, yielding 4.5 g (46.1%) of(±)-N-[(7,8-dihydro-2,3-dimethyl-6H-furo[3,2-h][1]benzopyran-8-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamineethanedioate(1:2); mp. 208.8° C. (comp. 7-a).

Residue (2) was repurified by column chromatography over silica gel(eluent:

CH₂ Cl₂ /CH₃ OH 85/15). The desired fractions were collected and thesolvent was evaporated. The residue (1.8 g) was dissolved in ethanol andconverted into the ethanedioic acid salt (1:2) with ethanedioic acid(0.010 mol). The precipitate was filtered off and dried, yielding 1.1 g(3.3%)(±)-N-2-pyrimidinyl-N'-[(3,6,7,8-tetrahydro-2,3-dimethyl-2H-furo[3,2-h][1]benzopyran-8-yl)methyl]-1,3-propanediamineethanedioate(1:2); mp. 171.2° C. (comp. 8-a).

The following compounds were prepared:

                  TABLE 2-a                                                       ______________________________________                                         ##STR13##                                                                    Co.  Ex.                                                                      No.  No.    R.sup.5, R.sup.6 Physical data                                    ______________________________________                                        1-a  6-a    --CH.sub.2 --CH.sub.2 --CH.sub.2 --O--                                                         mp. 190.4° C./.2(COOH).sub.2              2-a  6-a    --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                            mp. 118.2° C./                                                         .2HCl.1/2H.sub.2 O                               3-a  6-a    --O--CH.sub.2 --CH.sub.2 --O--                                                                 mp. 199.0° C./.2(COOH).sub.2              4-a  6-a    --O--CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                         mp. 197.6° C./                                                         .2(COOH).sub.2.H.sub.2 O                         5-a  7-a    --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                 mp. 57.6° C.                              6-a  7-a    --CH═CH--CH═CH--                                                                       mp. 226.3° C./.(COOH).sub.2               7-a  8-a    --C(CH.sub.3)═C(CH.sub.3)--O--                                                             mp. 208.8° C./.(COOH).sub.2               8-a  8-a    --CH(CH.sub.3)--CH(CH.sub.3)--O--                                                              mp. 171.2° C./.(COOH).sub.2               16-a 6-a    --O--CH.sub.2 --O--                                                                            mp. 169.3° C./                                                         .2(COOH).sub.2.1/2H.sub.2 O                      ______________________________________                                    

EXAMPLE 9-a

A mixture of intermediate (15-a) (0.02 mol) and 2-methylthioimidazolemonohydrochloride (0.02 mol) in ethanol (100 ml) was stirred andrefluxed for 16 hours. The solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃OH/(CH₃ OH/NH₃) 90/9/1). The pure fractions were collected and thesolvent was evaporated. The residue was dissolved in 2-propanol andconverted into the hydrochloric acid salt (1:2) with HCl/2-propanol. Thesalt was filtered off and dried, yielding 2.4 g of(±)-N-(4,5-dihydro-1H-imidazol-2-yl)-N'-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-1,3-propanediaminedihydrochloride hemihydrate; mp. 189.7° C. (comp. 9-a).

EXAMPLE 10-a

A mixture of compound (1-a) (0.0099 mol) in methanol (300 ml) washydrogenated with palladium on activated carbon (10%) (2 g) as acatalyst in the presence of a solution of thiophene (4%) (1 ml). Afteruptake of hydrogen (2 eq.), the catalyst was filtered off. The filtratewas evaporated and the residue was crystallized from methanol. Theprecipitate was filtered off and dried. This fraction was recrystallizedfrom methanol. The precipitate was filtered off and dried, yielding 0.9g (16.9%). The mother liquor was evaporated. The residue was dried,yielding 0.4 g (7.5%)(±)-N-[(2,3,4,7,8,9-hexahydrobenzo[2,1-b:3,4-b']dipyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamineethanedioate (1:2); mp. 226.9° C. (comp. 10-a).

                  TABLE 2-a                                                       ______________________________________                                         ##STR14##                                                                    Co.  Ex.                                                                      No.  No.    R.sup.5, R.sup.6 q   Physical data                                ______________________________________                                         9-a  9-a   --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                            1   mp. 189.7° C./                                                         .2HCl.1/2H.sub.2 O                           10-a 10-a   --CH.sub.2 --CH.sub.2 --CH.sub.2 --O--                                                         2   mp. 226.9° C./                                                         .2(COOH).sub.2                               11-a 10-a   --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                            2   mp. 210.0° C./.2HCl                   12-a 10-a   --O--CH.sub.2 --CH.sub.2 --O--                                                                 2   mp. 209.1° C./                                                         .2(COOH).sub.2                               13-a 10-a   --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 --                                                 2   .2HCl.2H.sub.2 O                             14-a 10-a   --C(CH.sub.3)═C(CH.sub.3)--O                                                               2   mp. 210.9° C./                                                         .2(COOH).sub.2                               15-a 10-a   --CH(CH.sub.3)═CH(CH.sub.3)--O                                                             2   mp. 206.4° C./                                                         .2(COOH).sub.2                               17-a 10-a   --O--CH.sub.2 --O--                                                                            2   mp. 199.1° C./                                                         .2(COOH).sub.2                               ______________________________________                                    

B. Preparation of Compounds of Formula (I) Wherein R⁵ and R⁶ DesignateR^(5b) and R^(6b) and the Intermediates Thereof

EXAMPLE 1-b

a) 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol (0.093 mol) wasdissolved in acetic acid (100 ml). Iodine monchloride (0.150 mol) waswarmed to 35° C. and added as a fluid to the solution of6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol in acetic acid. Thereaction mixture was stirred and refluxed for 24 h. The mixture wascooled, poured out onto ice (200 ml) and this mixture was extracted withCH₂ Cl₂. The separated organic layer was dried, filtered and evaporated.The residue was purified by flash column chromatography over silica gel(eluent: CH₂ Cl₂). The desired fractions were collected and the solventwas evaporated, yielding: 23.6 g (72.2%) of(±)-6-fluoro-3,4-dihydro-8-iodo-2H-1-benzopyran-2-methanolacetate(ester) (interm. 1-b).

b) Intermediate 1-b (0.035 mol) was dissolved in N,N-diethylethanamine(250 ml). N₂ was allowed to bubble through the solution during 15 min.Bis(triphenylphosphine)palladium (II) chloride (0.00042 mol) and cuprousiodide (0.0015 mol) were added. Trimethylsilylacetylene (0.056 mol) wasadded and the reaction mixture was stirred for 30 min at 50° C. (underN₂ flow). The blackened mixture was cooled and the solvent wasevaporated. The residue was dissolved in methanol saturated with ammonia(50 ml) and stirred for 4 hours at room temperature. The solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /CH₃ OH 97/3). The desired fractions(mixture of several compounds) were collected and the solvent wasevaporated. The residue (7.1 g) was dissolved in dichloromethane (150ml). N,N-diethylethanamine (15 ml) was added, followed by4-methylbenzenesulfonyl chloride (0.035 mol) and the reaction mixturewas stirred overnight at room temperature. Water (150 ml) was added. Theorganic layer was separated The aqueous layer was washed with CH₂ Cl₂(150 ml). The combined organic layers were dried (MgSO₄), filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂). The pure fractionswere collected and the solvent was evaporated, yielding 7.16 g (56.8%).This fraction was recrystallized from DIPE. The precipitate was filteredoff and dried, yielding 4.27 g (33.9%) of(±)-8-ethynyl-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol4-methylbenzenesulfonate(ester); mp. 120.2° C. (interm. 2-b).

In a similar manner was also prepared:

(±)-methyl3-[6-fluoro-3,4-dihydro-2-[[[(4-methylphenyl)sulfonyl]oxy]methyl]-2H-1-benzopyran-8-yl]-2-propenoate(interm. 3-b).

EXAMPLE 2-b

A suspension of (±)-methyl6fluoro-3,4-dihydro-8-iodo-2H-1-benzopyran-2-carboxylate (0.026 mol),(trifluoromethyl)trimethylsilane (0.081 mol), cuprous iodide (0.1 mol)and kalium fluoride (0.081 mol) in a mixture of DMF (50 ml) and1-methyl-2-pyrrolidinone (50 ml) was stirred for 3 h at 60° C. Thecooled reaction mixture was poured out into a solution of iron (III)chloride (200 g) and hydrochloric acid (50 ml) in water (300 ml). Thismixture was extracted three times with diethyl ether (150 ml). Thecombined organic layers were washed with a 5% aqueous Na₂ S₂ O₃ solution(decolorization), dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by flash column chromatography oversilica gel (eluent: CH₂ Cl₂). The pure fractions were collected and thesolvent was evaporated, yielding 5.7 g (78.8%). This fraction wasrecrystallized from DIPE. The precipitate was filtered off and dried,yielding 1.2 g(16.6%) (±)-methyl6-fluoro-3,4-dihydro-8-(trifluoromethyl)-2H-1-benzopyran-2-carboxylate;mp. 71.8° C. (interm 4-b).

EXAMPLE 3-b

a) A solution of intermediate 1-b (0.022 mol), 2-tributylstannyl furan(0.024 mol) and tetrakis(triphenylphoshine)palladium (0.0005 mol) in1-methyl-2-pyrrolidinone (50 ml) was stirred for 16 hours at 100° C. Thecooled reaction mixture was poured out into water (200 ml) and thismixture was extracted with DIPE (200 ml). The separated organic layerwas dried, filtered and the solvent was evaporated. The residue wasstirred in methanol saturated with ammonia (50 ml) for 16 hours. Thesolvent was evaporated The residue was purified by column chromatographyover silica gel (eluent: CH₂ Cl₂ /hexane 50/50, upgrading to pure CH₂Cl₂). The desired fractions were collected and the solvent wasevaporated, yielding 4.5 g (82.4%) of(±)-6-fluoro-8-(2-furanyl)-3,4-dihydro-2H-1-benzopyran-2-methanol(interm. 5-b).

b) 4-methylbenzenesulfonyl chloride (0.021 mol) was added to a solutionof intermediate 5-b (0.018 mol) in CH₂ Cl₂ (50 ml).N,N-diethylethanamine (5 ml) was added and the reaction mixture wasstirred for 24 hours at room temperature. The reaction mixture waspoured out into water and this mixture was extracted with CH₂ Cl₂. Theseparated organic layer was dried, filtered and the solvent wasevaporated The residue was purified by column chromatography over silicagel (eluent: CH₂ Cl₂ /hexane 50/50). The pure fractions were collectedand the solvent was evaporated. The residue was stirred in DIPE and thewhite precipitate was filtered off and dried, yielding: 5.2 g (71.8%) of(±)-6-fluoro-8-(2-furanyl)-3,4-dihydro-2H-1-benzopyran-2-methanol4-methylbenzenesulfonate(ester); mp.110.4° C. (interm. 6-b).

In a similar manner were also prepared:

(±)-6-fluoro-3,4-dihydro-8-(2-thienyl)-2H-1-benzopyran-2-methanol4-methylbenzenesulfonate(ester) (interm. 7-b);

(±)-6-fluoro-3,4-dihydro-8-phenyl-2H-1-benzopyran-2-methanol4-methylbenzenesulfonate(ester) (interm. 8-b);

(±)-6-fluoro-3,4-dihydro-8-(2-pyridinyl)-2H-1-benzopyran-2-methanol4-methylbenzenesulfonate(ester) (interm. 9-b);

(±)-8-(ethylthio)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanolmethanesulfonate(ester) ; mp. 107.7° C. (interm. 10-b); and

(±)-6-fluoro-3,4-dihydro-8-(phenylthio)-2H-1-benzopyran-2-methanolmethanesulfonate(ester) (interm. 11-b).

EXAMPLE 4-b

A solution of intermediate 11-b (0.016 mol) in dichloromethane (15 ml)was added dropwise to a mixture of Al₂ O₃ (16 g; neutral, wet) and 2KHSO₅.KHSO₄.K₂ SO₄ (0.016 mol) in dichloromethane (65 ml). The reactionmixture was stirred overnight at room temperature. The reaction mixturewas filtered, washed with CH₂ Cl₂ and the filtrate was dried (MgSO₄),filtered and the solvent evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH 97.5/2.5). Thedesired fractions were collected and the solvent was evaporated. Theresidue (7.2 g) was repurified by column chromatography over silica gel(eluent: CH₂ Cl₂, upgrading to CH₂ Cl₂ /(CH₃ OH/NH₃) 50/50). The purefractions were collected and the solvent was evaporated, yielding 3.8 g(61.8%) of(±)-6-fluoro-3,4-dihydro-8-(phenylsulfinyl)-2H-1-benzopyran-2-methanolmethanesulfonate(ester) (interm. 12-b).

EXAMPLE 5-b

a) (±)-Methyl 6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylate (0.26mol) was added to stirred nitric acid (300 ml). The reaction mixture wasstirred for 10 min at 40° C. The reaction mixture was stirred for 60 minat 60° C. The mixture was poured out into water. The resultingprecipitate was filtered off. The filtrate was extracted with CH₂ Cl₂.The separated organic layer was evaporated, leaving 33 g of residue,yielding 33 g of(±)-6-fluoro-3,4-dihydro-8-nitro-2H-1-benzopyran-2-carboxylic acid(interm. 13-b).

b) A 1M solution of (CH₃)₂ S.BH₃ in dichloromethane (0.28 mol) was addeddropwise to a mixture of intermediate 13-b (0.25 mol) in tetrahydrofuran(800 ml), stirred under N₂ flow. About 60 ml of the solvent was removedby distillation. The reaction mixture was stirred and refluxed for 2 h.The mixture was cooled, decomposed with CH₃ OH (20 ml), poured out intoH₂ O/NaOH and this mixture was extracted with CH₂ Cl₂. The separatedorganic layer was washed with water, dried (MgSO₄), filtered and thesolvent was evaporated, yielding 59 g of(±)-6-fluoro-3,4-dihydro-8-nitro-2H-1-benzopyran-2-methanol (104% cruderesidue) (interm. 14-b).

c) A mixture of intermediate 14-b (0.25 mol), 3,4-dihydro-2H-pyran (0.50mol) and hydrochloric acid in 2-propanol (0.5 ml) in trichloromethane(700 ml) was stirred for 3 h on a water bath. The reaction mixture waswashed with a 10% NaOH solution. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated, yielding 81 g of(±)-6-fluoro-3,4-dihydro-8-nitro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran(104% crude residue) (interm. 15-b).

d) A mixture of intermediate 15-b (0.47 mol) in methanol (600 ml) washydrogenated with palladium on activated carbon, palladium content 10%(5 g) as a catalyst in the presence of a 4% thiophene solution (3 ml).After uptake of H₂ (3 equiv), the catalyst was filtered off and thefiltrate was evaporated, yielding 130 g (98.3%) of(±)-6-fluoro-3,4-dihydro-2-[[(tetrahydro-2H-pyran-2-yl)oxy]methyl]-2H-1-benzopyran-8-amine(interm. 16-b).

e) A mixture of intermediate 16-b (0.036 mol),2,5-dimethoxytetrahydrofuran (0.22 mol) and PTSA (catalytic quantity) inDMF (140 ml) was stirred for 90 min at 100° C. The solvent wasevaporated. The residue was dissolved in CH₂ Cl₂. The organic solutionwas washed once with water, dried (MgSO₄), filtered and the solvent wasevaporated The residue was purified by column chromatography over silicagel (eluent: CH₂ Cl₂). The pure fractions were collected and the solventwas evaporated, yielding 6.6 g (55.3%) of(±)-6-fluoro-3,4-dihydro-8-(1H-pyrrol-1-yl)-2-[[(tetrahydro-2H-pyran-2-yl)oxy]-methyl]-2H-1-benzopyran(interm. 17-b).

f) A hydrochloric acid solution 10% (25 ml) was added to a mixture ofintermediate 17-b (0.019 mol) in methanol (65 ml). The reaction mixturewas stirred for 60 min at room temperature. The solvent was evaporated.The residue was partitioned between CH₂ Cl₂ and H₂ O. The organic layerwas separated, dried (MgSO₄), filtered and the solvent was evaporated.The residue was purified over silica gel on a glass filter (eluent: CH₂Cl₂ /CH₃ OH 98/2). The pure fractions were collected and the solvent wasevaporated, yielding: 3.4 g (72.4%) of(±)-6-fluoro-3,4-dihydro-8-(1H-pyrrol-1-yl)-2H-benzopyran-2-methanol(interm. 18-b).

g) N,N-diethylethanamine (7 ml) was added dropwise to a mixture ofintermediate 18-b (0.024 mol) and methanesulfonyl chloride (0.035 mol)in 2-propanone (30 ml), stirred and cooled on an ice bath. The reactionmixture was stirred for 1 hour. The mixture was filtered and thefiltrate was evaporated. The residue was dissolved in CH₂ Cl₂. Theorganic solution was washed with an aqueous hydrochloric acid solution,dried (MgSO₄), filtered and the solvent was evaporated, yielding 7.6 g(97.3%) of(±)-6-fluoro-3,4-dihydro-8-(1H-pyrrol-1-yl)-2H-1-benzopyran-2-methanolmethanesulfonate(ester) (interm. 19-b).

EXAMPLE 6-b

A solution of Br₂ (0.01 mol) in dichloromethane (50 ml) was addeddropwise to a solution of(±)-6-fluoro-3,4-dihydro-8-(2-thienyl)-2H-1-benzopyran-2-methanol4-methylbenzenesulfonate(ester) (0.01 mol) in dichloromethane (50 ml),stirred at 0° C. The reaction mixture was poured out into water. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was crystallized from DIPE. The precipitate wasfiltered off and dried, yielding 3.8 g (76.4%) of(±)-8-(5-bromo-2-thienyl)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol4-methylbenzenesulfonate(ester) (interm. 20-b).

EXAMPLE 7-b

Calcium oxide (5 g) was added to a solution of intermediate 2-b (0.0125mol) and N-2-pyrimidinyl-1,3-propanediamine (0.019 mol) intetrahydrofuran (10 ml) and the reaction mixture was stirred overnightat 150° C. (pressure vessel). The reaction mixture was cooled andfiltered. The filtrate was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂ Cl₂, upgrading to CH₂Cl₂ /CH₃ OH 90/10). Two desired fractions were collected and the solventwas evaporated, yielding 1.2 g of the pure fraction. This fraction wasdissolved in methanol (100 ml) and converted into the ethanedioic acidsalt (1:1) with etanedioic acid hydrate (0.620 g). The mixture wasconcentrated, 2-propanone was added and the resulting precipitate wasfiltered off and dried, yielding 1.2g (22.3%) of(±)-N-[(8-ethynyl-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamineethanedioate(1:1); mp. 201.1 C (comp. 1-b).

EXAMPLE 8-b

A solution of diisobutylaluminum hydride in methylbenzene (20%) (22 ml)was added dropwise to a solution of intermediate 4-b (0.018 mol) inmethylbenzene (50 ml), stirred at -70° C. This mixture was stirred for 1hour at -70° C. Methanol (10 ml) was added and the mixture was warmed toroom temperature, poured out into water, acidified with HCl, thenextracted with dichloromethane. The separated organic layer wasevaporated. A mixture of the residue andN-2-pyrimidinyl-1,3-propanediamine (0.014 mol) was hydrogenated withpalladium (2 g) as a catalyst in the presence of a solution of thiophene(4%) (2 ml). After uptake of hydrogen (250 ml), the catalyst wasfiltered off and the filtrate was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂ Cl₂ /CH₃ OH90/10). The pure fractions were collected and the solvent wasevaporated. The residue (2.2 g) was dissolved in ethanol (50 ml) andconverted into the ethanedioic acid salt (1:1) with ethanedioic acid(0.024 mol). The precipitate was filtered off and dried. This fractionwas recrystallized from methanol (±300 ml). The precipitate was filteredoff and dried, yielding 0.950 g (13.6%) of(±)-N-[[6-fluoro-3,4-dihydro-8-(trifluoromethyl)-2H-1-benzopyran-2-yl]methyl]-N'-2-pyrimidinyl-1,3-propanediamineethanedioate (1:1); mp. 216.3° C. (comp. 2-b).

EXAMPLE 9-b

A solution of the free base of compound (2-b) (0.00313 mol) andethanedioic acid dihydrate (0.00635 mol) in methanol (50 ml) washydrogenated for 2 hours at 50° C., with palladium on activated carbon(1 g) as a catalyst. After uptake of hydrogen (2 eq.), the catalyst wasfiltered off and the filtrate was concentrated. The resultingprecipitate was filtered (*) off and dried, yielding 0.310 g (17.2%) ofproduct The corresponding (*) filtrate was treated with 2-propanone andthe resulting precipitate was filtered off and dried, yielding 0.500 g(27.7%) of(±)-N-[[6-fluoro-3,4-dihydro-8-(trifluoromethyl)-2H-1-benzopyran-2-yl]methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamineethanedioate (1:2). hemihydrate; mp. 177.1° C. (comp. 3-b).

EXAMPLE 10-b

Reaction under N₂ flow. A solution of Bu₃ SnSCH₂ COOEt (0.011 mol) inmethylbenzene (40 ml) was added dropwise to a mixture of intermediate1-b (0.011 mol) and tetrakis(triphenylphosphine)palladium (0.00029 mol)in methylbenzene (160 ml). The reaction mixture was stirred and refluxedovernight. The reaction mixture was cooled, washed with a 10% KFsolution, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified over silica gel on a glass filter (eluent: CH₂ Cl₂/(CH₃ OH/NH₃) 95/5). The desired fractions were collected and thesolvent was evaporated. The residue was dissolved in 2-propanone andconverted into the ethanedioic acid salt (1:2). The precipitate wasfiltered off and dried (vacuum; 60° C.), yielding 4.4 g (65.1%) of(±)-ethyl[[6-fluoro-3,4-dihydro-2-[[[3-(2-pyrimidinylamino)propyl]amino]methyl]-2H-1-benzopyran-8-yl]thio]acetateethanedioate(1:2); mp. 154.4° C. (compound 17-b).

                                      TABLE 1-b                                   __________________________________________________________________________     ##STR15##                                                                    Co. No.                                                                           Ex. No.                                                                           R.sup.6b         Q           Physical data                            __________________________________________________________________________     1-b                                                                              1-b --C.tbd.CH       2-pyrimidinyl                                                                             mp. 201.1° C./.(COOH).sub.2        2-b                                                                              2-b --CF.sub.3       2-pyrimidinyl                                                                             mp. 216.3° C./.(COOH).sub.2        3-b                                                                              3-b --CF.sub.3                                                                                      ##STR16##  mp. 177.1° C./.2(COOH).sub.2.1                                         /2H.sub.2 O                               4-b                                                                              1-b --CH═CH--C(═O)OCH.sub.3                                                                2-pyrimidinyl                                                                             (E).2(COOH).sub.2                         5-b                                                                              1-b 2-furanyl        2-pyrimidinyl                                                                             mp. 192.8° C./.2(COOH).sub.2       6-b                                                                              1-b 2-thienyl        2-pyrimidinyl                                                                             mp. 205.8° C./.3/2(COOH).sub.2     7-b                                                                              3-b 2-thienyl                                                                                       ##STR17##  mp. 216.8° C./.2(COOH).sub.2       8-b                                                                              1-b 5-bromo-2-thienyl                                                                              2-pyrimidinyl                                                                             mp. 191.5° C./.2(COOH).sub.2       9-b                                                                              3-b --(CH.sub.2).sub.2 --C(O)--OCH.sub.3                                                            ##STR18##  mp. 209.6° C./.2(COOH).sub.2      10-b                                                                              1-b phenyl           2-pyrimidinyl                                                                             mp. 159.2° C./.2(COOH).sub.2      11-b                                                                              1-b 2-pyridinyl      2-pyrimidinyl                                                                             mp. 158.9° C./                                                         (E)-2-butenedioate(1:1)                  12-b                                                                              1-b --S--CH.sub.2 --CH.sub.3                                                                       2-pyrimidinyl                                                                             mp. 160.6° C./2(COOH).sub.2       13-b                                                                              1-b phenylthio       2-pyrimidinyl                                                                             mp. 181.0° C./2(COOH).sub.2       14-b                                                                              1-b phenylsulfinyl   2-pyrimidinyl                                                                             mp. 129.4° C./2(COOH).sub.2       15-b                                                                              1-b 1H-pyrrol-1-yl   2-pyrimidinyl                                                                             mp. 162.1° C./2(COOH).sub.2       16-b                                                                              3-b 1H-pyrrol-1-yl                                                                                  ##STR19##  mp. 177.7° C./.2(COOH).sub.2      17-b                                                                              4-b --S--CH.sub.2 --C(═O)--O--CH.sub.2 CH.sub.3                                                2-pyrimidinyl                                                                             mp. 154.4° C./2(COOH).sub.2       18-b                                                                              3-b 2-pyridinyl                                                                                     ##STR20##  mp. 186.3° C./.2(COOH).sub.2      __________________________________________________________________________

C. Preparation of the Compounds of Formula (I) Wherein R⁵ and R⁶designate R^(5c) and R^(6c) and the Intermediates Thereof

EXAMPLE 1-c

A mixture of 3,6-dichloropyridazine (0.168 mol), 1,3-propanediamine(0.84 mol) and sodium carbonate (0.17 mol) in ethanol (500 ml) wasstirred and refluxed overnight. The reaction mixture was filtered overdicalite. The filtrate was evaporated. The residue was crystallized fromacetonitrile. The crystals were filtered off and dried, yielding 20.7 gof N-(6-chloro-3-pyridazinyl)-1,3-propanediamine; mp. 124.9° C. (interm.1-c).

In a similar manner were also prepared:

N-3-pyridazinyl-1,3-propanediamine dihydrochloride; mp. 210.9° C.(interm. 2-c).

N-(6-methyl-3-pyridazinyl)-1,3-propanediamine (interm. 3-c).

EXAMPLE 2-c

a) A mixture of(±)-3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]propanenitrile(0.069 mol) in methanol (250 ml) was hydrogenated with Raney nickel (5g) as a catalyst. After uptake of hydrogen (2 eq.), the catalyst wasfiltered off and the filtrate was evaporated, yielding 20 g (94% cruderesidue) of(±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N-(phenylmethyl)-1,3-propanediamine(interm. 4-c).

b) A mixture of intermediate (4-c) (0.01 mol) and2-methylthio-4(1H-pyrimidinone (0.01 mol) was heated for 2 hours at 150°C. The residue was purified by column chromatography over silica gel(eluent: CH₂ Cl₂ /CH₃ OH 95/5). The pure fractions were collected andthe solvent was evaporated. The residue was converted into thehydrochloric acid salt (1:2) with HCl/2-propanol and crystallized from1,1'-oxybisethane. The salt was filtered off and dried, yielding 2.8 g(56.5%) of(±)-2-[[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]propyl]amino]-4(1H)-pyrimidinonedihydrochloride monohydrate; mp. 150.2° C. (interm. 5-c).

In a similar manner were prepared:

                  TABLE 1-c                                                       ______________________________________                                         ##STR21##                                                                    Int.                                                                          No.  Alk       Q            Physical data                                     ______________________________________                                         5-c --(CH.sub.2).sub.3 --                                                                   4-hydroxy-2- mp. 150.2° C./.2HCl.H.sub.2 O                             pyrimidinyl                                                     6-c --(CH.sub.2).sub.2 --                                                                   4-hydroxy-6- mp. 212.1° C./.2HCl                                       methyl-2-                                                                     pyrimidinyl                                                     7-c --(CH.sub.2).sub.2 --                                                                   4-hydroxy-6-propyl-                                                                        mp. 190.5° C./.2HCl                                       2-pyrimidinyl                                                   8-c --(CH.sub.2).sub.3 --                                                                   2-pyrazinyl     --                                              9-c --(CH.sub.2).sub.3 --                                                                   5-chloro-2-  mp. 111.3° C./.2HCl.1/2H.sub.2 O                          pyridinyl                                                      10-c --(CH.sub.2).sub.3 --                                                                   2-chloro-4-     --                                                            pyrimidinyl                                                    11-c --(CH.sub.2).sub.3 --                                                                   2-methoxy-4-    --                                                            pyrimidinyl                                                    12-c --(CH.sub.2).sub.3 --                                                                   2-(dimethylamino)-                                                                            --                                                            4-pyrimidinyl                                                  13-c --(CH.sub.2).sub.3 --                                                                   2-(1-piperidinyl)-                                                                            --                                                            4-pyrimidinyl                                                  14-c --(CH.sub.2).sub.3 --                                                                   2-(methylamino)-                                                                              --                                                            4-pyrimidinyl                                                  ______________________________________                                    

EXAMPLE 3-c

a) A mixture of 2-chlorocarbonyl-3,4-dihydro-2H-1-benzopyran (0.47 mol)in N,N-dimethylacetamide (100 ml), a solution of thiophene (4%) (3 ml)and 2,2'-oxybispropane (400 ml) was hydrogenated with palladium onactivated carbon (10%) (5 g) as a catalyst. After uptake of hydrogen (1eq.), the catalyst was filtered off and the filtrate was evaporated. Theresidue, potassium acetate (20 g) and benzenemethanamine (50 g) inN,N-dimethylacetamide (2 ml) and methanol (300 ml) was hydrogenated withpalladium on activated carbon (10%) (5 g) as a catalyst. After uptake ofhydrogen (1 eq.), the catalyst was filtered off and the filtrate wasevaporated. The residue in methanol (500 ml) was hydrogenated withpalladium on activated carbon (10%) (5 g) as a catalyst. After uptake ofhydrogen (1 eq.), the catalyst was filtered off and the filtrate wasevaporated. The residue was taken up in 1,1'-oxybisethane and washedwith a NaOH-solution. The organic layer was dried (MgSO₄), filtered offand evaporated. The residue (70 g) was distilled at 70° C. (0.1 mm Hg),yielding 48.7 g (63.5%) of (±)-3,4-dihydro-2H-1-benzopyran-2-methanamine(interm. 15-c).

b) A mixture of intermediate (15-c) (0.12 mol) and 2-propenenitrile(0.12 mol) in ethanol (235 ml) was stirred and refluxed for 4 hours. Thesolvent was evaporated, yielding 27 g crude residue of(±)-3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propanenitrile(interm. 16-c).

c) A mixture of intermediate (16-c) (0.12 mol) in methanol saturatedwith ammonia (500 ml) was hydrogenated with Raney nickel (6 g) as acatalyst After uptake of hydrogen (2 eq.), the catalyst was filtered offand the filtrate was evaporated. The residue was purified bydistillation, yielding 24 g (90.8%) of(±)-N-[(3,4-dihydro-2H-benzopyran-2-yl)methyl]-1,3-propanediamine(interm. 17-c).

B. Preparation of the Final Compounds (-c)

EXAMPLE 4-c

A mixture of intermediate (1-c) (0.058 mol),3,4-dihydro-2H-1-benzopyran-2-carboxaldehyde (0.064 mol) and potassiumacetate (7.1 g) in methanol (200 ml) was hydrogenated with platinum onactivated carbon 5% (2 g) as a catalyst in the presence of a solution ofthiophene (4%) (1 ml). After uptake of hydrogen (1 eq.), the catalystwas filtered off. The filtrate was evaporated. The residue was dissolvedin H₂ O/CH₂ Cl₂ and alkalized with NaOH. The organic layer wasseparated, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂ Cl₂ /CH₃ OH 90/10). Two fractions were collected. The first fractionwas evaporated. The residue was crystallized from 2-propanol. Thecrystals were filtered off and dried. The second fraction was evaporatedand the residue was crystallized from 2-propanol. The crystals werefiltered off and dried, yielding 3.09 g (16%) of(±)-N-(6-chloro-3-pyridazinyl)-N'-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-1,3-propanediamine;mp. 107.8° C. (comp. 1-c).

EXAMPLE 5-c

Intermediate (5-c) (0.005 mol) was hydrogenated in methanol (250 ml)with palladium on activated carbon (2 g) as a catalyst. After uptake ofhydrogen (1 eq.), the catalyst was filtered off. The solvent wasevaporated. The residue (2 g) was recrystallized from methanol. Thecrystals were filtered off and dried, yielding 0.7 g (36%) of(±)-2-[[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]amino]-4(1H)-pyrimidinonedihydrochloride (comp. 8-c).

EXAMPLE 6-c

A mixture of intermediate (17-c) (0.03 mol) and2-methylthio-4(1H)-pyrimidinone (0.03 mol) in 2-methoxyethanol (50 ml)was stirred and refluxed overnight The solvent was evaporated. Theresidue was stirred in water and extracted with dichloromethane. Theseparated organic layer was dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂ Cl₂ /(CH₃ OH/NH₃) 95/5). The pure fractions werecollected and the solvent was evaporated. This fraction was dissolved in2-propanone and converted into the ethanedioic acid salt (2:3). The saltwas filtered off and crystallized from methanol. The solid (1.2 g) wasfiltered off and dried, yielding 1.0 g (7.4%) of(±)-2-[[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]amino]-4(3H)-pyrimidinoneethanedioate(2:3); mp. 206.7° C. (comp. 9-c).

EXAMPLE 7-c

A mixture of (±)-N²-[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]N⁴,N.sup.4-dimethyl-2,4-pyrimidinediamine dihydrochloride (0.0067 mol) in methanol(150 ml) was hydrogenated with palladium on activated carbon 10% (2 g)as a catalyst in the presence of a solution of hydrochloric acid in2-propanol (2 ml). After uptake of hydrogen (2 eq.), the catalyst wasfiltered off. The filtrate was evaporated and the residue wascrystallized twice from methanol. The crystals were filtered off anddried, yielding 0.32 g (13.1%) of(±)-2-[[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]amino]-5,6-dihydro-4(3H)-pyrimidinonedihydrochloride; mp. 273.6° C. (comp. 12-c).

EXAMPLE 8-c

A mixture of compound (17-c) (0.02 mol) in methanol (200 ml) washydrogenated with palladium on activated carbon 10% (2 g) as a catalyst.After uptake of hydrogen (2 eq.), the catalyst was filtered off. Thefiltrate was evaporated. The residue was dissolved in 2-propanol andconverted into the hydrochloric acid salt (1:2) with HCl/2-propanol. Thesalt was filtered off and dried, yielding 5.61 g (75%) of(±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(3,4,5,6-tetrahydro-2-pyridinyl)-1,3-propanediaminedihydrochloride; mp. 211.1° C. (comp. 15-c).

EXAMPLE 9-c

A mixture of the free base of compound (19-c) (0.0145 mol) and Raneynickel (5 g) in tetrahydrofuran (150 ml) was stirred and refluxed for 1hour. The catalyst was filtered off and the filtrate was evaporated. Theresidue was dissolved in 2-propanone and converted into the ethanedioicacid salt (1:2). The salt was filtered off (3 g) and recrystallized frommethanol (600 ml). The crystals were filtered off and dried, yielding2.5 g (36.2%) of(±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-4-pyrimidinyl-1,3-propanediamineethanedioate(1:2); mp. 222.2° C. (comp. 20-c).

                  TABLE 2-c                                                       ______________________________________                                         ##STR22##                                                                    Co.  Ex.                                                                      No.  No.    R.sup.A   R.sup.42  Physical data                                 ______________________________________                                         1-c 4-c    H         Cl        mp. 107.8° C.                           2-c 4-c    H         H         mp. 169.7° C.                                                          .2HCl.1/2H.sub.2 O                             3-c 4-c    H         CH.sub.3  mp. 158.7° C./                                                         .2HCl.1/2H.sub.2 O                             4-c 4-c    H         Cl        mp. 203.1° C./[α].sub.D.sup.2                                    0 =                                                                           -48.51° (c = 1% in                                                     methanol)/(-)-(R).2HCl                         5-c 4-c    6-F       Cl        mp. 229.3° C./[α].sub.D.sup.2                                    0 =                                                                           -27.00° (c = 1% in                                                     methanol)/(-)-(R).2HCl                         6-c 4-c    6-F       Cl        mp. 243.2° C./[α].sub.D.sup.2                                    0 =                                                                           +33.67° (c = 1% in                                                     methanol)/(+)-(S).2HCl                         7-c 6-c    7-CH.sub.2 --CH.sub.3                                                                   Cl        mp. 223.9° C./.2HCl                    25-c 4-c    8-OCH.sub.3                                                                             Cl        mp. 182.6° C./                                                         .2HCl.H.sub.2 O                               26-c 5-c    H         CN        mp. 192.3° C./(COOH).sub.2             27-c 5-c    H         OH        mp. 191.1° C./(COOH).sub.2             28-c 5-c    H         --C(═O)--NH.sub.2                                                                   mp. 211.7° C./(COOH).sub.2             ______________________________________                                    

                  TABLE 3-c                                                       ______________________________________                                         ##STR23##                                                                    Co.  Ex.                                                                      No.  No.    R.sup.A                                                                             R.sup.2                                                                           R.sup.1                                                                           Alk     R.sup.B Physical data                       ______________________________________                                         8-c 5-c    H     H   H   --(CH.sub.2).sub.3 --                                                                 H       .2HCl                                9-c 6-c    H     H   H   --(CH.sub.2).sub.3 --                                                                 H       mp. 206.7° C./                                                         .3/2(COOH).sub.2                    10-c 6-c    H     H   H   --(CH.sub.2).sub.2 --                                                                 (CH.sub.2).sub.2 CH.sub.3                                                             mp. 227.9° C./                                                         .2HCl                               11-c 6-c    H     H   H   --(CH.sub.2).sub.2 --                                                                 H       mp. 227.6° C./                                                         .2HCl                               ______________________________________                                    

                  TABLE 4-c                                                       ______________________________________                                         ##STR24##                                                                    Co. No                                                                              Ex. No.    R.sup.A                                                                              R.sup.2                                                                            R.sup.1                                                                            Physical data                               ______________________________________                                        12-c  7-c        H      H    H    mp. 273.6° C./.2HCl                  ______________________________________                                    

                  TABLE 5-c                                                       ______________________________________                                         ##STR25##                                                                    Co.   Ex.                                                                     No.   No.    R.sup.A                                                                             R.sup.2                                                                           R.sup.1                                                                           Alk     R.sup.B                                                                           Physical data                          ______________________________________                                        13-c  6-c    6-F   H   H   --(CH.sub.2).sub.3 --                                                                 H   mp. 198.1° C./.2HCl             14-c  5-c    H     H   H   --(CH.sub.2).sub.3 --                                                                 H   mp. 188.9° C./.2HCl             ______________________________________                                    

                  TABLE 6-c                                                       ______________________________________                                         ##STR26##                                                                    Co.   Ex.                                                                     No.   No.    R.sup.A                                                                             R.sup.2                                                                           Alk     R.sup.B                                                                           n   Physical data                          ______________________________________                                        15-c  8-c    H     H   --(CH.sub.2).sub.3 --                                                                 H   2   mp. 211.1° C./.2HCl             ______________________________________                                    

                                      TABLE 7-c                                   __________________________________________________________________________     ##STR27##                                                                    Co.                                                                              Ex.                                                                        No.                                                                              No.                                                                              R.sup.A                                                                         R.sup.2                                                                         Alk   R.sup.1                                                                         R.sup.B                                                                           R.sup.C                                                                              Physical data                                    __________________________________________________________________________    16-c                                                                             4-c                                                                              H H --(CH.sub.2).sub.3 --                                                               H H   H      mp. 182.6° C./.2HCl                       17-c                                                                             4-c                                                                              H H --(CH.sub.2).sub.3 --                                                               H 6-CH.sub.3                                                                        3-C(═O)NH.sub.2                                                                  mp. 246.9° C./.2HCl.H.sub.2 O             __________________________________________________________________________

                                      TABLE 8-c                                   __________________________________________________________________________     ##STR28##                                                                    Co. No.                                                                           Ex. No.                                                                           R.sup.A                                                                         R.sup.2                                                                            R.sup.1                                                                         Alk   R.sup.B                                                                             Physical data                                    __________________________________________________________________________    18-c                                                                               6-c                                                                              H H    H --(CH.sub.2).sub.3 --                                                               --S--CH.sub.3                                                                       mp. 225.8° C./.2(COOH).sub.2              19-c                                                                              10-c                                                                              H H    H --(CH.sub.2).sub.3 --                                                               H     mp. 222.2° C./.2(COOH).sub.2              20-c                                                                              10-c                                                                              H CH.sub.2 CH.sub.3                                                                  H --(CH.sub.2).sub.3 --                                                               H     mp. 117.4° C./.2(COOH).sub.2                                           .1/2 H.sub.2 O                                   21-c                                                                               5-c                                                                              H H    H --(CH.sub.2).sub.3 --                                                               --O--CH.sub.3                                                                       mp. 179.6° C./.2(COOH).sub.2              22-c                                                                               5-c                                                                              H H    H --(CH.sub.2).sub.3 --                                                               --N(CH.sub.3).sub.2                                                                 mp. 204.6° C./.2(COOH).sub.2              23-c                                                                               5-c                                                                              H H    H --(CH.sub.2).sub.3 --                                                               1-piperidinyl                                                                       mp. 206.8° C./.2(COOH).sub.2              24-c                                                                               5-c                                                                              H H    H --(CH.sub.2).sub.3 --                                                               --NH--CH.sub.3                                                                      mp. 188.1° C./.2(COOH).sub.2              __________________________________________________________________________

                                      TABLE 9-c                                   __________________________________________________________________________     ##STR29##                                                                    Co. No.                                                                           Ex. No.                                                                           R.sup.A                                                                         Q                 Physical data                                     __________________________________________________________________________    29-c                                                                              5-c 6-F                                                                             2-thiazolyl       mp. 145.3° C./.2 HCl                       30-c                                                                              5-c H                                                                                ##STR30##        mp. 156.2° C.                              31-c                                                                              5-c H                                                                                ##STR31##        mp. 214.1° C.                              32-c                                                                              5-c H                                                                                ##STR32##        mp. 184.9° C./(COOH).sub.2                 33-c                                                                              6-c H                                                                                ##STR33##        mp. 168.2° C.                              __________________________________________________________________________

                                      TABLE 10-c                                  __________________________________________________________________________     ##STR34##                                                                                                     Physical data                                Co. No.                                                                           Ex. No.                                                                           R.sup.1                                                                          R.sup.A                                                                             R.sup.B     R.sup.C                                                                           (mp in ° C.)/base/salt                __________________________________________________________________________    34-c                                                                              6-c H  CN    2-phenylethyl                                                                             methyl                                                                            159.4/.2(COOH).sub.2                         35-c                                                                              9-c H  H     2-phenylethyl                                                                             methyl                                                                            198.5                                        36-c                                                                              6-c H  CN    (2-methoxyphenyl)methyl                                                                   methyl                                                                            166.1/(COOH).sub.2                           37-c                                                                              9-c H  H     (2-methoxyphenyl)methyl                                                                   methyl                                                                            191.9/2HCl                                   38-c                                                                              6-c H  CN    4-methyl-1-piperazinyl                                                                        171.6                                        39-c                                                                              6-c CH.sub.3                                                                         CN    phenylmethyl                                                                              methyl                                                                            142.9/(COOH).sub.2                           40-c                                                                              9-c H  H     cyclohexyl  H   242.5/2HCl                                   41-c                                                                              9-c H  C(═O)NH.sub.2                                                                   cyclohexyl  H   201.5/2HCl                                   __________________________________________________________________________

D. Pharmacological Example

EXAMPLE 1-d

Segments of basilar arteries taken from pigs (anaesthetised with sodiumpentobarbital) were mounted for recording of isometric tension in organbaths. The preparations were bathed in Krebs-Henseleit solution. Thesolution was kept at 37° C. and gassed with a mixture of 95% O₂ -5% CO₂.The preparations were stretched until a stable basal tension of 2 gramswas obtained.

The preparations were made to constrict with serotonin (3×10⁻⁷ M ). Theresponse to the addition of serotonin was measured and subsequently theserotonin was washed away. This procedure was repeated until stableresponses were obtained.

Subsequently the test compound was administered to the organ bath andthe constriction of the preparation was measured. This constrictiveresponse was expressed as a percentage of the response to serotonin asmeasured previously.

The lowest active concentration was defined as the concentration atwhich 50% of the response to serotonin is obtained.

In table 3 the lowest active concentration of compounds of formula (I)are presented.

                  TABLE 1-d                                                       ______________________________________                                        Co. No.   Lowest active concentration (M)                                     ______________________________________                                        1-a       3 · 10.sup.-8                                              2-a       3 · 10.sup.-7                                              4-a       1 · 10.sup.-6                                              5-a       3 · 10.sup.-7                                              9-a       1 · 10.sup.-8                                              10-a      3 · 10.sup.-9                                              11-a      3 · 10.sup.-8                                              12-a      3 · 10.sup.-8                                              13-a      3 · 10.sup.-7                                              ______________________________________                                    

                  TABLE 2-d                                                       ______________________________________                                        Co. No.   Lowest active concentration (M)                                     ______________________________________                                        1-b       1 · 10.sup.-7                                              3-b       3 · 10.sup.-7                                              4-b       3 · 10.sup.-8                                              5-b       3 · 10.sup.-8                                              6-b       1 · 10.sup.-7                                              7-b       3 · 10.sup.-9                                              ______________________________________                                    

                  TABLE 3-d                                                       ______________________________________                                        Co. no.   Lowest active concentration (M)                                     ______________________________________                                         1-c      1 · 10.sup.-6                                               3-c      1 · 10.sup.-7                                               4-c      1 · 10.sup.-7                                               5-c      3 · 10.sup.-7                                              12-c      1 · 10.sup.-6                                              13-c      <3 · 10.sup.-7                                             14-c      1 · 10.sup.-7                                              15-c      3 · 10.sup.-8                                              16-c      1 · 10.sup.-6                                              18-c      1 · 10.sup.-7                                              19-c      3 · 10.sup.-7                                              21-c      1 · 10.sup.-7                                              22-c      1 · 10.sup.-6                                              23-c      3 · 10.sup.-7                                              24-c      3 · 10.sup.-8                                              ______________________________________                                    

E. Composition Examples

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I), a pharmaceutically acceptable acid additionsalt or a stereochemically isomeric form thereof.

EXAMPLE 1-e Oral Drops

500 Grams of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acidand 1.5 l of the polyethylene glycol at 60˜80° C. After cooling to30˜40° C. there were added 35 l of polyethylene glycol and the mixturewas stirred well. Then there was added a solution of 1750 grams ofsodium saccharin in 2.5 l of purified water and while stirring therewere added 2.5 l of cocoa flavor and polyethylene glycol q.s. to avolume of 50 l, providing an oral drop solution comprising 10 mg/ml ofA.I. The resulting solution was filled into suitable containers.

EXAMPLE 2-e Oral Solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3l of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

EXAMPLE 3-e Capsules

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatincapsules, comprising each 20 mg of the active ingredient.

EXAMPLE 4-e Film-coated Tablets

Preparation of Tablet Core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about200 ml of water. The wet powder mixture was sieved, dried and sievedagain. Then there was added 100 grams microcrystalline cellulose and 15grams hydrogenated vegetable oil. The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each containing 10 mg ofthe active ingredient.

Coating

To a solution of 10 grams methyl cellulose in 75 ml of denaturatedethanol there was added a solution of 5 grams of ethyl cellulose in 150ml of dichloromethane. Then there were added 75 ml of dichloromethaneand 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol wasmolten and dissolved in 75 ml of dichloromethane. The latter solutionwas added to the former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentratedcolour suspension and the whole was homogenated. The tablet cores werecoated with the thus obtained mixture in a coating apparatus.

EXAMPLE 5-e Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 l of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.I.The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 l, giving a solution comprising 4 mg/ml of A.I.The solution was sterilized by filtration (U.S.P. XVII p. 811) andfilled in sterile containers.

EXAMPLE 6-e Suppositories

Grams A.I. was dissolved in a solution of 3 grams2,3-eihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Gramssurfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad 300 gramswere molten together. The latter mixture was mixed well with the formersolution. The thus obtained mixture was poured into moulds at atemperature of 37-38° C. to form 100 suppositories each containing 30mg/ml of the A.I.

EXAMPLE 7-e Injectable Solution

60 Grams of A.I. and 12 grams of benzylalcohol were mixed well andsesame oil was added q.s. ad 1 l, giving a solution comprising 60 mg/mlof A.I. The solution was sterilized and filled in sterile containers.

What is claimed is:
 1. A compound having the formula ##STR35## apharmaceutically acceptable acid or base addition salt thereof, or astereochemically isomeric form thereof, whereinR¹, R² and R³ eachindependently are hydrogen or C₁₋₆ alkyl; R⁴ is hydrogen, halo, C₁₋₆-allyl, hydroxy, C₁₋₆ alkyloxy, aryloxy or arylmethoxy, R⁵ and R⁶designate R^(5a) and R^(6a),wherein R^(5a) and R^(6a) are taken togetherto form a bivalent radical, which is linked to the 7 and 8 position ofthe dihydrobenzopyran moiety, and has the formula ##STR36## in thesebivalent radicals one or two hydrogen atoms may be substituted with C₁₋₆alkyl, C₁₋₆ alkylcarbonyl or C₁₋₆ alkyl-S(O)--, n is 3 or 4; each Xindependently is --O--, --S--, --S(O)--, --S(O)₂ --, --C(O)--, --NR₇ --;each Y independently is --O--, --S--, --S(O)--, --S(O)₂ --, --C(O)--,--NR₇ --; Z is --O--C(O)--, --C(O)--O--, --NH--C(O)--, --C(O)--NH--,eacht independently is 1 or 2; R⁷ is hydrogen, C₁₋₆ alkyl, C₁₋₆alkylcarbonyl or C₁₋₆ alkyl-S(O)--,each A independently is hydroxy, C₁₋₆alkyl, C₁₋₆ alkyloxy, or R⁵ and R⁶ designate R^(5b) and R^(6b), whereinR^(5b) is hydrogen and R^(6b) is hydroxyC₁₋₆ alkyl, carboxylC₁₋₆ alkyl,C₁₋₆ alkyloxycarbonylC₁₋₆ alkyl, trihalomethyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkyloxycarbonylC₁₋₆ alkyl-S--, carboxylC₁₋₆ -alkyl-S--, C₁₋₆ alkyl-S--,C₁₋₆ alkyl-S(O)--, aryl-S--, aryl-S(O)-- or R^(6b) is a radical offormula ##STR37## R⁸ and R⁹ each independently are hydrogen, carboxyl,C₁₋₆ alkyloxycarbonyl, aminocarbonyl, mono- or di(C₁₋₆alkyl)aminocarbonyl; R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ eachindependently are hydrogen, halo or C₁₋₆ alkyl; R¹⁸, R¹⁹, R²⁰, R²¹, R²²,R²³, R²⁴ and R²⁵ each independently are hydrogen or C₁₋₆ alkyl; or R⁵and R⁶ designate R^(5c) and R^(6c) in which case R⁴ can only meanhydrogen; and R^(5c) and R^(6c) each independently are hydrogen, halo,C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, hydroxy, C₁₋₆ alkyloxy, cyano,aminoC₁₋₆ alkyl, carboxyl, C₁₋₆ alkyloxycarbonyl, nitro, amino,aminocarbonyl, C₁₋₆ alkylcarbonylamino, or mono- or di(C₁₋₆ alkyl)amino,Alk¹ is C₁₋₅ alkanediyl, Alk² is C₂₋₁₅ alkanediyl; Q is a radical offormula ##STR38## wherein R²⁶ is hydrogen, cyano, aminocarbonyl or C₁₋₆alkyl; R²⁷ is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, C₃₋₆cycloalkyl or arylC₁₋₆ alkyl; R²⁸ is hydrogen or C₁₋₆ alkyl; or R²⁷ andR²⁸ taken together form a bivalent radical of formula --(CH₂)₄ --,--(CH₂)₅ --, or a piperazine which is optionally substituted with C₁₋₆alkyl; R²⁹, R³⁰, R³¹, R³⁶, R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵,R⁴⁶, R⁵³, R⁵⁴ and R⁵⁵ each independently are hydrogen, hydroxy, halo,C₁₋₆ alkyl, C₁₋₆ allkyloxy, aryloxy, arylC₁₋₆ alkyl, C₁₋₆ alkylthio,cyano, amino, mono- or di(C₁₋₆ alkyl)amino, mono- or di(C₃₋₆cycloalkyl)amino, aminocarbonyl, C₁₋₆ alkyloxycarbonylamino, C₁₋₆alkylaminocarbonylamino, piperidinyl, pyrrolidinyl, R³², R³⁵ and R⁵²each independently are hydrogen, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, orarylC₁₋₆ alkyl; q is 1, 2 or 3, R³³ and R³⁴ are each hydrogen or takentogether with the carbon atom to which they are connected they can formC(O); r is 1, 2 or 3, R⁴⁷ and R⁴⁸ are each hydrogen or taken togetherwith the carbon atom to which they are connected they can form C(O); R⁴⁹is hydrogen, halo or C₁₋₆ alkyl; R⁵⁰ is hydrogen and R⁵¹ is hydroxy; orR⁵⁰ and R⁵¹ taken together may form a bivalent radical of formula (CH₂)₃or (CH₂)₄ which is optionally substituted with C₁₋₆ alkyl; aryl isphenyl optionally substituted with hydroxy, halo, C₁₋₆ alkyl, C₁₋₆alkyloxy;with the proviso that when R⁴ is hydrogen and R⁵ and R⁶designate R^(5c) and R^(6c) then Q must be a radical of formula (gg);(hh); (ii), (jj); (kk); (ll); (mm); (nn); a radical of formula (aa)wherein R²⁷ is C₃₋₆ cycloalkyl or arylC₁₋₆ alkyl; a radical of formula(aa) wherein R²⁷ and R²⁸ taken together with the nitrogen atom to whichthey are attached form a piperazine which is optionally substituted withC₁₋₆ alkyl; a radical of formula (bb) wherein R²⁹ is hydroxy on a carbonatom adjacent to a nitrogen atom; a radical of formula (dd) wherein R³⁵is hydrogen and R³³ and R³⁴ taken together with the carbon atom to whichthey are attached form C(O); a radical of formula (ee) wherein R⁵⁵ isarylC₁₋₆ alkyl.
 2. A compound as claimed in claim 1 wherein R¹, R², R³and R⁴ are as defined in claim 1 and whereinR⁵ and R⁶ designate R^(5b)and R^(6b), wherein R^(5b) is hydrogen and R^(6b) is hydroxyC₁₋₆ alkyl,carboxylC₁₋₆ alkyl, C₁₋₆ alkyloxycarbonylC₁₋₆ alkyl, trihalomethyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkyloxycarbonylC₁₋₆ alkyl-S--, carboxylC₁₋₆alkyl-S--, C₁₋₆ alkyl-S--, C₁₋₆ alkyl-S(O)--, aryl-S--, aryl-S(O)-- orR^(6b) is a radical of formula ##STR39## R⁸ and R⁹ each independentlyare hydrogen, carboxyl, C₁₋₆ alkyloxycarbonyl, aminocarbonyl, mono- ordi(C₁₋₆ alkyl)aminocarbonyl; R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷each independently are hydrogen, halo or C₁₋₆ alkyl; R¹⁸, R¹⁹, R²⁰, R²¹,R²², R²³, R²⁴ and R²⁵ each independently are hydrogen or C₁₋₆ alkyl; orR⁵ and R⁶ designate R^(5c) and R^(6c) in which case R⁴ can only meanhydrogen; and R^(5c) and R^(6c) each independently are hydrogen, halo,C₁₋₆ alkyl, C₃₋₆ alkenyl, C₃₋₆ alkynyl, hydroxy, C₁₋₆ alkyloxy, cyano,aminoC₁₋₆ alkyl, carboxyl, C₁₋₆ alkyloxycarbonyl, nitro, amino,aminocarbonyl, C₁₋₆ alkylcarbonylamino, or mono- or di(C₁₋₆ alkyl)amino.3. A compound as claimed in claim 1 wherein R¹, R², R³ and R⁴ are asdefined in claim 1 and wherein R⁵ and R⁶ designate R^(5a) and R^(6a),wherein in formulas (a7) and (a8) t is 2; Q is a radical of formula(aa), (bb), (cc), (dd) wherein q is 1 or 2, (ee) wherein R⁵⁵ ishydrogen, (ff), (gg), (hh), (ii), (jj), (kk) wherein q is 1 or 2, (ll).4. A compound as claimed in claim 1, wherein wherein R¹, R², R³ are asdefined in claim 1, R⁴ is hydrogen, halo, C₁₋₆ alkyl; R⁵ and R⁶designate R^(5b) and R^(6b), R^(5b) being hydrogen and R^(6b) ishydroxyC₁₋₆ alkyl, carboxylC₁₋₆ alkyl, C₁₋₆ alkyloxycarbonylC₁₋₆ alkyl,trihalomethyl, a radical of formula (b1), (b2), (b3), (b4), (b5), (b6),(b7), (b8), (b9), (b10), (b11), (b12); Q is a radical of formula (aa),(bb), (cc), (dd) wherein q is 1 or 2, (ee) wherein R⁵⁵ is hydrogen,(ff), (gg), (hh), (ii), (jj), (kk) wherein q is 1 or 2, or (ll).
 5. Acompound as claimed in claim 1 wherein R¹, R², R³ are as defined inclaim 1, R⁴ is hydrogen and R⁵ and R⁶ designate R^(5c) and R^(6c), and Qis a radical of formula (gg); (hh); (ii); (jj); (kk) wherein q is 1 or2; (ll); a radical of formula (bb) wherein R²⁹ is hydroxy on a carbonatom adjacent to a nitrogen atom; or a radical of formula (dd) whereinR³⁵ is hydrogen and R³³ and R³⁴ taken together with the carbon atom towhich they are attached form C(O) and q is 1 or
 2. 6. A compound asclaimed in claim 1, wherein the compoundisN-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine;N-[(3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine;N-(4,5-dihydro-1H-imidazol-2-yl)-N'-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-1,3-propanediamine;N-[(2,3,4,7,8,9-hexahydrobenzo[2,1-b:3,4-b']dipyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-[(2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-[(2,3,7,8-tetrahydro-9H-pyrano[2,3-f]-1,4-benzodioxin-9-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-[(3,4,7,8,9,10-hexahydro-2H-naphtho[1,2-b]pyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;methyl3-[6-fluoro-3,4-dihydro-2-[[[3-(2-pyrimidinylamino)propyl]amino]methyl]-2H-1-benzopyran-8-yl]-2-propenoate;N-[[6-fluoro-8-(2-furanyl)-3,4-dihydro-2H-1-benzopyran-2-yl]methyl]-N'-2-pyrimidinyl-1,3-propanediamine;N-[[6-fluoro-3,4-dihydro-8-(2-thienyl)-2H-1-benzopyran-2-yl]methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine;N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(3,4,5,6-tetrahydro-2-pyridinyl)-1,3-propanediamine,N⁴ -[3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]amino]propyl]-N²-methyl-2,4-pyrimidinediamine; a pharmaceutically acceptable acidaddition salt, or stereochemically isomeric form thereof.
 7. Acomposition comprising a pharmaceutically acceptable carrier and as anactive ingredient a therapeutically amount of a compound as claimed inclaim
 1. 8. A process of preparing a composition as claimed in claim 7,comprising intimately mixing a therapeutically effective amount of thecompound with a pharmaceutically acceptable carrier.
 9. An intermediateof formula (V-a), a pharmaceutically acceptable addition salt thereof ora stereochemically isomeric form thereof, wherein R³, R^(5a) and R^(6a)are as defined in claim 1 and wherein alk³ is C₁₋₄ alkanediyl.##STR40##10.
 10. A process of preparing a compound as claimed in claim1, comprising a) reacting an intermediate of formula (II), wherein R¹,R², R³, R⁴, R⁵, R⁶, R⁷, Alk¹ and Alk² are as defined in claim 1, with areagent of formula (III), wherein Q is as defined in claim 1 and W¹ is areactive leaving group; ##STR41## b) reducing an acyl derivative offormula (IV), wherein R³, R⁴, R⁵ and R⁶ is as defined in claim 1, Alk³is C₁₋₄ alkanediyl, and reductively N-alkylating an intermediate offormula (VI), wherein R¹, R², Alk² and Q are as defined in claim 1 withthe resulting aldehyde of formula (V) ##STR42## c) N-alkylating an amineof formula (VI) with an intermediate of formula (VII), wherein R³, R⁴R⁵, R⁶ and Alk¹ are as defined in claim 1 and W² is a reactive leavinggroup, ##STR43## d) reductive N-alkylating an amine of formula (IX),wherein R², R³, R⁴, R⁵, R⁶ and Alk¹ are defined in claim 1, with analdehyde of formula (X), wherein R¹ and Q are as defined in claim 1 andAlk⁴ is C₂₋₁₄ alkanediyl; ##STR44## and optionally converting thecompounds of formula (I) into each other by a functional grouptransformation reaction; and, if desired, converting a compound offormula (I) into a therapeutically active non-toxic acid addition salt,or conversely, converting an acid addition salt into a free base formwith alkali; and/or preparing stereochemically isomeric forms thereof.11. A method for inducing vasoconstriction in a patient in need thereofwhich comprises administering to the patient an effective amount of acompound as claimed in claim
 1. 12. A method for treating migraine in apatient in need thereof which comprises administering to the patient aneffective amount of a compound as claimed in claim
 1. 13. A method fortreating hypotension in a patient in need thereof which comprisesadministering to the patient an effective amount of a compound asclaimed in claim
 1. 14. A method for venous insufficiency in a patientin need thereof which comprises administering to the patient aneffective amount of a compound as claimed in claim 1.